Compositions useful for treating disorders related to kit

ABSTRACT

Compounds and compositions useful for treating disorders related to KIT and PDFGR are described herein.

CLAIM OF PRIORITY

This application is a continuation of U.S. Ser. No. 14/517,480 filedOct. 17, 2014, which claims priority to U.S. Ser. No. 61/892,077 filedOct. 17, 2013, each of which is incorporated herein in its entirety.

BACKGROUND

The invention relates to compounds and compositions useful for treatingdisorders related to KIT and PDGFR.

The enzyme KIT (also called CD117) is a receptor tyrosine kinaseexpressed on a wide variety of cell types. The KIT molecule contains along extracellular domain, a transmembrane segment, and an intracellularportion. The ligand for KIT is stem cell factor (SCF), whose binding tothe extracellular domain of KIT induces receptor dimerization andactivation of downstream signaling pathways. KIT mutations generallyoccur in the DNA encoding the juxtumembrane domain (exon 11). They alsooccur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18.Mutations make KIT function independent of activation by SCF, leading toa high cell division rate and possibly genomic instability. Mutant KIThas been implicated in the pathogenesis of several disorders andconditions including systemic mastocytosis, GIST (gastrointestinalstromal tumors), AML (acute myeloid leukemia), melanoma, and seminoma.As such, there is a need for therapeutic agents that inhibit KIT, andespecially agents that inhibit mutant KIT.

Platelet-derived growth factor receptors (PDGF-R) are cell surfacetyrosine kinase receptors for members of the platelet-derived growthfactor (PDGF) family. PDGF subunits-A and -B are important factorsregulating cell proliferation, cellular differentiation, cell growth,development and many diseases including cancer. A PDGFRA D842V mutationhas been found in a distinct subset of GIST, typically from the stomach.The D842V mutation is known to be associated with tyrosine kinaseinhibitor resistance. As such, there is a need for agents that targetthis mutation.

SUMMARY OF THE INVENTION

The present invention provides compounds and compositions for treatingor preventing conditions such as mastocytosis by modulating the activityof Kit, such compounds having the structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is selected from hydrogen, halo and

wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclicor bicyclic heteroaryl, cycloalkyl and heterocyclyl;

each X and Y is independently selected from CR¹ and N;

Z is selected from C₁-C₆ alkyl, cycloalkyl, monocyclic or bicyclic aryl,monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl,monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclicheterocyclylalkyl; wherein each of C₁-C₆ alkyl, cycloalkyl, monocyclicor bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic orbicyclic heterocyclylalkyl is substituted with 0-5 occurrences of R^(C);

L is selected from a bond, —(C(R²)(R²))_(m)—, —(C₂-C₆ alkynylene)-,—(C₂-C₆ alkenylene)-, —(C₁-C₆ haloalkylene)-, —(C₁-C₆ heteroalkylene)-,—(C₁-C₆ hydroxyalkylene)-, —C(O)—, —O—, —S—, —S(O), —SO₂—, —N(R²)—,—O—(C₁-C₆ alkylene)-, —(C₁-C₆ alkylene)-O—, —N(R²)—CO—, —CO—N(R²)—,—(C₁-C₆ alkylene)-N(R²)—, —N(R²)—(C₁-C₆ alkylene)-, —N(R²)—CO—(C₁-C₆alkylene)-, —CO—N(R²)—(C₁-C₆ alkylene)-, —N(R²)—SO₂—, —SO₂—N(R²)—,—N(R²)—SO₂—(C₁-C₆ alkylene)-, and —SO₂—N(R²)—(C₁-C₆ alkylene)-;

each R^(A) and R^(B) is independently selected from C₁-C₆ alkyl, halo,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, monocyclic orbicyclic aralkyl, —N(R²)(R²), cyano, and —OR²;

each R^(C) is independently selected from C₁-C₆ alkyl, C₁-C₆ alkynyl,halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic orbicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano,—C(O)R², —OC(O)R², —C(O)OR², —SR², —S(O)₂R², —S(O)₂—N(R²)(R²), —(C₁-C₆alkylene)-S(O)₂—N(R²)(R²), —N(R²)(R²), —C(O)—N(R²)(R²),—N(R²)(R²)—C(O)R², —(C₁-C₆ alkylene)-N(R²)—C(O)R², —NR²S(O)₂R²,—P(O)(R²)(R²), and —OR²; wherein each of heteroalkyl, haloalkyl,haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl,heterocyclyl, and heterocyclylalkyl is substituted with 0-5 occurrencesof R^(a); or 2 R^(C) together with the carbon atom(s) to which they areattached form a cycloalkyl or heterocyclyl ring substituted with 0-5occurrences of R^(a);

each R¹ is independently selected from hydrogen, C₁-C₆ alkyl, monocyclicaralkyl, C₁-C₆ hydroxyalkyl, halo, C₁-C₆ haloalkyl, —N(R²)(R²), and—OR²;

each R² is independently selected from hydrogen, hydroxyl, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl; wherein each of C₁-C₆ alkyl,cycloalkyl and heterocyclyl is substituted with 0-5 occurrences ofR^(b), or 2 R² together with the carbon or nitrogen atom to which theyare attached form a cycloalkyl or heterocyclyl ring;

each R^(a) and R^(b) is independently selected from halo, hydroxyl,—C(O)R′, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆hydroxyalkyl, —NR′R′, and cycloalkyl; wherein cycloalkyl is substitutedwith 0-5 occurrences of R′;

R′ is hydrogen, hydroxyl, or C₁-C₆ alkyl; and

m, p, and q are each independently 0, 1, 2, 3, or 4.

Any of the compounds disclosed herein may be used to treat any of thediseases disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a line graph depicting tumor growth curves for the differenttreatment groups: vehicle (

), Dasatinib at 25 milligrams per kilogram (mpk) orally twice a day (pobid) (

), Compound 165 at 25 mpk po bid (

), Compound 165 at 50 mpk po bid (

), and Compound 165 at 100 mpk po bid (

).

DETAILED DESCRIPTION OF THE INVENTION

“Aliphatic group” means a straight-chain, branched-chain, or cyclichydrocarbon group and includes saturated and unsaturated groups, such asan alkyl group, an alkenyl group, and an alkynyl group.

“Alkylene” refers to a divalent radical of an alkyl group, e.g., —CH₂—,—CH₂CH₂—, and CH₂CH₂CH₂—.

“Alkenyl” means an aliphatic group containing at least one double bond.

“Alkoxyl” or “alkoxy” means an alkyl group having an oxygen radicalattached thereto. Representative alkoxyl groups include methoxy, ethoxy,propyloxy, tert-butoxy and the like.

“Alkyl” refers to a monovalent radical of a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂ alkyl, C₁-C₁₀alkyl, and C₁-C₆ alkyl, respectively. Exemplary alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

“Alkynyl” refers to a straight or branched hydrocarbon chain containing2-12 carbon atoms and characterized in having one or more triple bonds.Examples of alkynyl groups include, but are not limited to, ethynyl,propargyl, and 3-hexynyl. One of the triple bond carbons may optionallybe the point of attachment of the alkynyl substituent.

“Hydroxyalkylene” or “hydroxyalkyl” refers to an alkylene or alkylmoiety in which an alkylene or alkyl hydrogen atom is replaced by ahydroxyl group. Hydroxyalkylene or hydroxyalkyl includes groups in whichmore than one hydrogen atom has been replaced by a hydroxyl group.

“Aromatic ring system” is art-recognized and refers to a monocyclic,bicyclic or polycyclic hydrocarbon ring system, wherein at least onering is aromatic.

“Aryl” refers to a monovalent radical of an aromatic ring system.Representative aryl groups include fully aromatic ring systems, such asphenyl, naphthyl, and anthracenyl, and ring systems where an aromaticcarbon ring is fused to one or more non-aromatic carbon rings, such asindanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and thelike.

“Arylalkyl” or “aralkyl” refers to an alkyl moiety in which an alkylhydrogen atom is replaced by an aryl group. Aralkyl includes groups inwhich more than one hydrogen atom has been replaced by an aryl group.Examples of “arylalkyl” or “aralkyl” include benzyl, 2-phenylethyl,3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.

“Aryloxy” refers to —O-(aryl), wherein the heteroaryl moiety is asdefined herein.

“Halo” refers to a radical of any halogen, e.g., —F, —Cl, —Br, or —I.

“Haloalkyl” and “haloalkoxy” refers to alkyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine.

“Heteroalkyl” refers to an optionally substituted alkyl, which has oneor more skeletal chain atoms selected from an atom other than carbon,e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range may be given, e.g. C₁-C₆ heteroalkyl which refers to thenumber of carbons in the chain, which in this example includes 1 to 6carbon atoms. For example, a —CH₂OCH₂CH₃ radical is referred to as a“C₃” heteroalkyl. Connection to the rest of the molecule may be througheither a heteroatom or a carbon in the heteroalkyl chain.

“Carbocyclic ring system” refers to a monocyclic, bicyclic or polycyclichydrocarbon ring system, wherein each ring is either completelysaturated or contains one or more units of unsaturation, but where noring is aromatic.

“Carbocyclyl” refers to a monovalent radical of a carbocyclic ringsystem. Representative carbocyclyl groups include cycloalkyl groups(e.g., cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like),and cycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl,cyclopentadienyl, and the like).

“Cycloalkyl” refers to a cyclic, bicyclic, tricyclic, or polycyclicnon-aromatic hydrocarbon groups having 3 to 12 carbons. Anysubstitutable ring atom can be substituted (e.g., by one or moresubstituents). The cycloalkyl groups can contain fused or spiro rings.Fused rings are rings that share a common carbon atom. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

“Cycloalkylalkyl” refers to a -(cycloalkyl)-alkyl radical wherecycloalkyl and alkyl are as disclosed herein. The “cycloalkylalkyl” isbonded to the parent molecular structure through the cycloalkyl group.

“Heteroaromatic ring system” is art-recognized and refers to monocyclic,bicyclic or polycyclic ring system wherein at least one ring is botharomatic and comprises at least one heteroatom (e.g., N, O or S); andwherein no other rings are heterocyclyl (as defined below). In certaininstances, a ring which is aromatic and comprises a heteroatom contains1, 2, 3, or 4 ring heteroatoms in such ring.

“Heteroaryl” refers to a monovalent radical of a heteroaromatic ringsystem. Representative heteroaryl groups include ring systems where (i)each ring comprises a heteroatom and is aromatic, e.g., imidazolyl,oxazolyl, isoxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl,thiophenyl pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,indolizinyl, purinyl, naphthyridinyl, and pteridinyl; (ii) each ring isaromatic or carbocyclyl, at least one aromatic ring comprises aheteroatom and at least one other ring is a hydrocarbon ring or e.g.,indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,pyrido[2,3-b]-1,4-oxazin-3-(4H)-one, 5,6,7,8-tetrahydroquinolinyl and5,6,7,8-tetrahydroisoquinolinyl; and (iii) each ring is aromatic orcarbocyclyl, and at least one aromatic ring shares a bridgeheadheteroatom with another aromatic ring, e.g., 4H-quinolizinyl.

“Heterocyclic ring system” refers to monocyclic, bicyclic and polycyclicring systems where at least one ring is saturated or partiallyunsaturated (but not aromatic) and comprises at least one heteroatom. Aheterocyclic ring system can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted.

“Heterocyclyl” refers to a monovalent radical of a heterocyclic ringsystem. Representative heterocyclyls include ring systems in which (i)every ring is non-aromatic and at least one ring comprises a heteroatom,e.g., tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl,tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl;(ii) at least one ring is non-aromatic and comprises a heteroatom and atleast one other ring is an aromatic carbon ring, e.g.,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (iii)at least one ring is non-aromatic and comprises a heteroatom and atleast one other ring is aromatic and comprises a heteroatom, e.g.,3,4-dihydro-1H-pyrano[4,3-c]pyridine, and1,2,3,4-tetrahydro-2,6-naphthyridine. In some embodiments, heterocyclylcan include:

“Heterocyclylalkyl” refers to an alkyl group substituted with aheterocycle group.

“Cyano” refers to a —CN radical.

“Nitro” refers to —NO₂.

“Hydroxy” or “hydroxyl” refers to —OH.

“Substituted”, whether preceded by the term “optionally” or not, meansthat one or more hydrogens of the designated moiety are replaced with asuitable substituent. Unless otherwise indicated, an “optionallysubstituted” group may have a suitable substituent at each substitutableposition of the group, and when more than one position in any givenstructure may be substituted with more than one substituent selectedfrom a specified group, the substituent may be either the same ordifferent at each position. Combinations of substituents envisionedunder this invention are preferably those that result in the formationof stable or chemically feasible compounds. The term “stable”, as usedherein, refers to compounds that are not substantially altered whensubjected to conditions to allow for their production, detection, and,in certain embodiments, their recovery, purification, and use for one ormore of the purposes disclosed herein.

As used herein, the definition of each expression, e.g., alkyl, m, n,etc., when it occurs more than once in any structure, is intended to beindependent of its definition elsewhere in the same structure.

Certain compounds of the present invention may exist in particulargeometric or stereoisomeric forms. The present invention contemplatesall such compounds, including cis- and trans-isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as falling within thescope of the invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound, as well as enantiomeric mixtures thereof.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.ee=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%.

The compounds or compositions described herein may contain anenantiomeric excess of at least 50%, 75%, 90%, 95%, or 99% of one formof the compound, e.g., the S-enantiomer. In other words such compoundsor compositions contain an enantiomeric excess of the S enantiomer overthe R enantiomer.

The compounds described herein may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example deuterium (²H), tritium (³H),carbon-13 (¹³C), or carbon-14 (¹⁴C). All isotopic variations of thecompounds disclosed herein, whether radioactive or not, are intended tobe encompassed within the scope of the present invention. In addition,all tautomeric forms of the compounds described herein are intended tobe within the scope of the invention.

The compound can be useful as the free base or as a salt. Representativesalts include the hydrobromide, hydrochloride, sulfate, bisulfate,phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate,laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts and the like. (See, forexample, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.)

Certain compounds disclosed herein can exist in unsolvated forms as wellas solvated forms, including hydrated forms. The term “hydrate” or“hydrated” as used herein, refers to a compound formed by the union ofwater with the parent compound.

In general, the solvated forms are equivalent to unsolvated forms andare encompassed within the scope of the present invention. Certaincompounds disclosed herein may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present invention and are intended to be withinthe scope of the present invention.

As used herein, the term “patient” refers to organisms to be treated bythe methods of the present invention. Such organisms preferably include,but are not limited to, mammals (e.g., murines, simians, equines,bovines, porcines, canines, felines, and the like), and most preferablyincludes humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

Compounds

In one embodiment, the invention provides a compound having structuralFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

W is selected from hydrogen, halo and

wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclicor bicyclic heteroaryl, cycloalkyl and heterocyclyl;

each X and Y is independently selected from CR¹ and N;

Z is selected from C₁-C₆ alkyl, cycloalkyl, monocyclic or bicyclic aryl,monocyclic or bicyclic aralkyl, monocyclic or bicyclic heteroaryl,monocyclic or bicyclic heterocyclyl, and monocyclic or bicyclicheterocyclylalkyl; wherein each of C₁-C₆ alkyl, cycloalkyl, monocyclicor bicyclic aryl, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheteroaryl, monocyclic or bicyclic heterocyclyl, and monocyclic orbicyclic heterocyclylalkyl is substituted with 0-5 occurrences of R^(C);

L is selected from a bond, —(C(R²)(R²))_(m)—, —(C₂-C₆ alkynylene)-,—(C₂-C₆ alkenylene)-, —(C₁-C₆ haloalkylene)-, —(C₁-C₆ heteroalkylene)-,—(C₁-C₆ hydroxyalkylene)-, —C(O)—, —O—, —S—, —S(O), —SO₂—, —N(R²)—,—O—(C₁-C₆ alkylene)-, —(C₁-C₆ alkylene)-O—, —N(R²)—CO—, —CO—N(R²)—,—(C₁-C₆ alkylene)-N(R²)—, —N(R²)—(C₁-C₆ alkylene)-, —N(R²)—CO—(C₁-C₆alkylene)-, —CO—N(R²)—(C₁-C₆ alkylene)-, —N(R²)—SO₂—, —SO₂—N(R²)—,—N(R²)—SO₂—(C₁-C₆ alkylene)-, and —SO₂—N(R²)—(C₁-C₆ alkylene)-;

each R^(A) and R^(B) is independently selected from C₁-C₆ alkyl, halo,C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, monocyclic orbicyclic aralkyl, —N(R²)(R²), cyano, and —OR²;

each R^(C) is independently selected from C₁-C₆ alkyl, C₁-C₆ alkynyl,halo, C₁-C₆ heteroalkyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆hydroxyalkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic orbicyclic aryloxy, monocyclic or bicyclic aralkyl, monocyclic or bicyclicheterocyclyl, monocyclic or bicyclic heterocyclylalkyl, nitro, cyano,—C(O)R², —OC(O)R², —C(O)OR², —SR², —S(O)₂R², —S(O)₂—N(R²)(R²), —(C₁-C₆alkylene)-S(O)₂—N(R²)(R²), —N(R²)(R²), —C(O)—N(R²)(R²),—N(R²)(R²)—C(O)R², —(C₁-C₆ alkylene)-N(R²)—C(O)R², —NR²S(O)₂R²,—P(O)(R²)(R²), and —OR²; wherein each of heteroalkyl, haloalkyl,haloalkoxy, alkyl, alkynyl, cycloalkyl, aryl, aryloxy, aralkyl,heterocyclyl, and heterocyclylalkyl is substituted with 0-5 occurrencesof R^(a); or 2 R^(C) together with the carbon atom(s) to which they areattached form a cycloalkyl or heterocyclyl ring substituted with 0-5occurrences of R^(a);

each R¹ is independently selected from hydrogen, C₁-C₆ alkyl, monocyclicaralkyl, C₁-C₆ hydroxyalkyl, halo, C₁-C₆ haloalkyl, —N(R²)(R²), and—OR²;

each R² is independently selected from hydrogen, hydroxyl, halo, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, and heterocyclylalkyl; wherein each of C₁-C₆ alkyl,cycloalkyl and heterocyclyl is substituted with 0-5 occurrences ofR^(b), or 2 R² together with the carbon or nitrogen atom to which theyare attached form a cycloalkyl or heterocyclyl ring;

each R^(a) and R^(b) is independently selected from halo, hydroxyl,—C(O)R′, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ heteroalkyl, C₁-C₆hydroxyalkyl, —NR′R′, and cycloalkyl; wherein cycloalkyl is substitutedwith 0-5 occurrences of R′;

R′ is hydrogen, hydroxyl, or C₁-C₆ alkyl; and

m, p, and q are each independently 0, 1, 2, 3, or 4.

In some embodiments, W is H. In some embodiments, W is halo. In someembodiments, W is

wherein Ring A is selected from monocyclic or bicyclic aryl, monocyclicor bicyclic heteroaryl, cycloalkyl and heterocyclyl. In someembodiments, Ring A is selected from phenyl, cycloalkyl, monocyclicheteroaryl, and heterocyclyl. In some embodiments, Ring A is optionallysubstituted phenyl. In some embodiments, Ring A is substituted phenyl.In some embodiments, Ring A is unsubstituted phenyl. In someembodiments, Ring A is phenyl substituted with halo.

In some embodiments, each R^(A) is independently selected from C₁-C₆alkyl, halo, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —N(R²)(R²), cyano, and—OR². In some embodiments, R^(A) is independently selected from C₁-C₆alkyl and halo. In some embodiments, q is 0, 1 or 2.

In some embodiments, each R^(B) is independently selected from C₁-C₆alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, —N(R²)(R²), cyano and—OR². In some embodiments, each R^(B) is independently selected fromC₁-C₆ alkyl and C₁-C₆ hydroxyalkyl. In some embodiments, p is 0, 1 or 2.In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, at least one of X and Y is N. In some embodiments,X and Y are both N. In some embodiments, X and Y are both CR¹. In someembodiments, X and Y are both CH.

In some embodiments, Z is C₁-C₆ alkyl. In some embodiments, Z iscycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl,monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl,or monocyclic or bicyclic heterocyclylalkyl; wherein each of C₁-C₆alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclicaralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclicheterocyclyl, and monocyclic and bicyclic heterocyclylalkyl issubstituted with 0-5 occurrences of R^(C). In some embodiments, Z isbicyclic heteroaryl, bicyclic heterocyclyl, monocyclic heteroaryl,monocyclic heterocyclylalkyl, or monocyclic aryl. In some embodiments, Zis aryl or heteroaryl substituted with 0-5 occurrences of R^(C). In someembodiments, Z is phenyl substituted with 0-5 occurrences of R^(C). Insome embodiments, Z is phenyl substituted with 1 or 2 occurrences ofR^(C). In some embodiments, Z is phenyl substituted with —N(R²)(R²),C₁-C₆ alkyl, or C₁-C₆ hydroxyalkyl. In some embodiments, Z is heteroarylsubstituted with 0-5 occurrences of R^(C). In some embodiments, Z is aheteroaryl ring substituted with 0-5 occurrences of R^(C).

In some embodiments, each R^(C) is independently selected from C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic orbicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl,—C(O)R², —C(O)OR², —SR², —S(O)₂R², and —OR²; wherein each ofheteroalkyl, alkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl issubstituted with 0-5 occurrences of R^(a).

In some embodiments, L is selected from a bond, —O—, —(C(R²)(R²))_(m)—,—O—(C₁-C₆ alkylene)-, —(C₁-C₆ alkylene)-O—, —(C₂-C₆ alkynylene)-,—(C₁-C₆ haloalkylene)-, —(C₁-C₆ hydroxyalkylene)-, —S—, —S(O), —SO₂—,and —N(R²)—. In some embodiments, L is selected from a bond,—(C(R²)(R²))_(m)—, —S—, and —SO₂—. In some embodiments, L is—(C(R²)(R²))_(m)—. In some embodiments, L is a bond or CH₂. In someembodiments, L is —(C(R²)(R²))_(m)—, wherein each R² is independentlyselected from hydrogen, hydroxyl, —NR″R″, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, and cycloalkyl; and m is 1 or 2.

In some embodiments, the compound is a compound of Formula II, or apharmaceutically acceptable salt thereof, where the substituents are asdefined above.

In some embodiments, L is —(C(R²)(R²))_(m)—. In some embodiments, X andY are CR¹. In some embodiments, Z is phenyl, Z is pyridinyl, Z isisoxazolyl, Z is pyrazolyl, or Z is dihydroisoquinolinyl.

In some embodiments, Ring A is selected from monocyclic or bicyclicaryl, monocyclic or bicyclic heteroaryl, cycloalkyl and heterocyclyl. Insome embodiments, Ring A is selected from phenyl, cycloalkyl, monocyclicheteroaryl, and heterocyclyl. In some embodiments, Ring A is optionallysubstituted phenyl. In some embodiments, Ring A is substituted phenyl.In some embodiments, Ring A is unsubstituted phenyl. In someembodiments, Ring A is phenyl substituted with halo.

In some embodiments, each R^(A) is independently selected from C₁-C₆alkyl, halo, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —N(R²)(R²), cyano, and—OR². In some embodiments, R^(A) is independently selected from C₁-C₆alkyl and halo. In some embodiments, q is 0, 1 or 2.

In some embodiments, each R^(B) is independently selected from C₁-C₆alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, —N(R²)(R²), cyano and—OR². In some embodiments, each R^(B) is independently selected fromC₁-C₆ alkyl and C₁-C₆ hydroxyalkyl. In some embodiments, p is 0, 1 or 2.In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, at least one of X and Y is N. In some embodiments,X and Y are both N. In some embodiments, X and Y are both CR¹. In someembodiments, X and Y are both CH.

In some embodiments, Z is C₁-C₆ alkyl. In some embodiments, Z iscycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl,monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl,or monocyclic or bicyclic heterocyclylalkyl; wherein each of C₁-C₆alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclicaralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclicheterocyclyl, and monocyclic and bicyclic heterocyclylalkyl issubstituted with 0-5 occurrences of R^(C). In some embodiments, Z isbicyclic heteroaryl, bicyclic heterocyclyl, monocyclic heteroaryl,monocyclic heterocyclylalkyl, or monocyclic aryl. In some embodiments, Zis aryl or heteroaryl substituted with 0-5 occurrences of R^(C). In someembodiments, Z is phenyl substituted with 0-5 occurrences of R^(C). Insome embodiments, Z is phenyl substituted with 1 or 2 occurrences ofR^(C). In some embodiments, Z is phenyl substituted with —N(R²)(R²),C₁-C₆ alkyl, or C₁-C₆ hydroxyalkyl. In some embodiments, Z is heteroarylsubstituted with 0-5 occurrences of R^(C). In some embodiments, Z is aheteroaryl ring substituted with 0-5 occurrences of R^(C).

In some embodiments, each R^(C) is independently selected from C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic orbicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl,—C(O)R², —C(O)OR², —SR², —S(O)₂R², and —OR²; wherein each ofheteroalkyl, alkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl issubstituted with 0-5 occurrences of R^(a).

In some embodiments, L is selected from a bond, —O—, —(C(R²)(R²))_(m)—,—O—(C₁-C₆ alkylene)-, —(C₁-C₆ alkylene)-O—, —(C₂-C₆ alkynylene)-,—(C₁-C₆ haloalkylene)-, —(C₁-C₆ hydroxyalkylene)-, —S—, —S(O), —SO₂—,and —N(R²)—. In some embodiments, L is selected from a bond,—(C(R²)(R²))_(m)—, —S—, and —SO₂—. In some embodiments, L is—(C(R²)(R²))_(m)—. In some embodiments, L is a bond or CH₂. In someembodiments, L is —(C(R²)(R²))_(m)—, wherein each R² is independentlyselected from hydrogen, hydroxyl, —NR″R″, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, and cycloalkyl; and m is 1 or 2.

In other embodiments, the compound is a compound of Formula II(a), or apharmaceutically acceptable salt thereof, where the substituents are asdefined above.

In some embodiments, Z is phenyl, Z is pyridinyl, Z is isoxazolyl, Z ispyrazolyl, or Z is dihydroisoquinolinyl. In some embodiments, R^(C) ispiperidinyl.

In some embodiments, each R^(A) is independently selected from C₁-C₆alkyl, halo, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —N(R²)(R²), cyano, and—OR². In some embodiments, R^(A) is independently selected from C₁-C₆alkyl and halo. In some embodiments, q is 0, 1 or 2.

In some embodiments, each R^(B) is independently selected from C₁-C₆alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ heteroalkyl, —N(R²)(R²), cyano and—OR². In some embodiments, each R^(B) is independently selected fromC₁-C₆ alkyl and C₁-C₆ hydroxyalkyl. In some embodiments, p is 0, 1 or 2.In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, at least one of X and Y is N. In some embodiments,X and Y are both N. In some embodiments, X and Y are both CR¹. In someembodiments, X and Y are both CH.

In some embodiments, Z is C₁-C₆ alkyl. In some embodiments, Z iscycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclic aralkyl,monocyclic or bicyclic heteroaryl, monocyclic or bicyclic heterocyclyl,or monocyclic or bicyclic heterocyclylalkyl; wherein each of C₁-C₆alkyl, cycloalkyl, monocyclic or bicyclic aryl, monocyclic or bicyclicaralkyl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclicheterocyclyl, and monocyclic and bicyclic heterocyclylalkyl issubstituted with 0-5 occurrences of R^(C). In some embodiments, Z isbicyclic heteroaryl, bicyclic heterocyclyl, monocyclic heteroaryl,monocyclic heterocyclylalkyl, or monocyclic aryl. In some embodiments, Zis aryl or heteroaryl substituted with 0-5 occurrences of R^(C). In someembodiments, Z is phenyl substituted with 0-5 occurrences of R^(C). Insome embodiments, Z is phenyl substituted with 1 or 2 occurrences ofR^(C). In some embodiments, Z is phenyl substituted with —N(R²)(R²),C₁-C₆ alkyl, or C₁-C₆ hydroxyalkyl. In some embodiments, Z is heteroarylsubstituted with 0-5 occurrences of R^(C). In some embodiments, Z is aheteroaryl ring substituted with 0-5 occurrences of R^(C).

In some embodiments, each R^(C) is independently selected from C₁-C₆alkyl, C₁-C₆ heteroalkyl, C₁-C₆ hydroxyalkyl, cycloalkyl, monocyclic orbicyclic heterocyclyl, monocyclic or bicyclic heterocyclylalkyl,—C(O)R², —C(O)OR², —SR², —S(O)₂R², and —OR²; wherein each ofheteroalkyl, alkyl, cycloalkyl, heterocyclyl, and heterocyclylalkyl issubstituted with 0-5 occurrences of R^(a).

The invention also features pharmaceutical compositions comprising apharmaceutically acceptable carrier and any compound of Formulas I-III.

The table below shows the structures of compounds described herein.

Compound Number Structure 1

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Synthesis

Compounds of the invention, including salts and N-oxides thereof, can beprepared using known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below. The reactions for preparing compounds of theinvention can be carried out in suitable solvents which can be readilyselected by one of skill in the art of organic synthesis. Suitablesolvents can be substantially non-reactive with the starting materials(reactants), the intermediates, or products at the temperatures at whichthe reactions are carried out, e.g., temperatures which can range fromthe solvent's freezing temperature to the solvent's boiling temperature.A given reaction can be carried out in one solvent or a mixture of morethan one solvent. Depending on the particular reaction step, suitablesolvents for a particular reaction step can be selected by the skilledartisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Wuts and Greene,Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: NewJersey, (2006), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance (NMR) spectroscopy (e.g., ¹Hor ¹³C), infrared (IR) spectroscopy, spectrophotometry (e.g.,UV-visible), mass spectrometry (MS), or by chromatographic methods suchas high performance liquid chromatography (HPLC) or thin layerchromatography (TLC).

Indications

The compounds described herein can be useful for treating conditionsassociated with aberrant KIT activity, in humans or non-humans.Activating mutations in KIT are found in multiple indications, includingsystemic mastocytosis, GIST (gastrointestinal stromal tumors), AML(acute myeloid leukemia), melanoma, seminoma, intercranial germ celltumors, and mediastinal B-cell lymphoma.

Mastocytosis refers to a group of disorders characterized by excessivemast cell accumulation in one tissue, or in multiple tissues.Mastocytosis is subdivided into two groups of disorders: (1) cutaneousmastocytosis (CM) describes forms that are limited to the skin; and (2)systemic mastocytosis (SM) describes forms in which mast cellsinfiltrate extracutaneous organs, with or without skin involvement. SMis further subdivided into five forms: indolent (ISM), smoldering (SSM),aggressive (ASM), SM with associated hemotologic non-mast cell lineagedisease (SM-AHNMD), and mast cell leukemia (MCL).

Diagnosis of systemic mastocytosis is based in part on histological andcytological studies of bone marrow showing infiltration by mast cells offrequently atypical morphology, which frequently abnormally expressnon-mast cell markers (CD25 and/or CD2). Diagnosis of SM is confirmedwhen bone marrow mast cell infiltration occurs in the context of one ofthe following: (1) abnormal mast cell morphology (spindle-shaped cells);(2) elevated level of serum tryptase above 20 ng/mL; or (3) the presenceof the activating KIT D816V mutation.

Activating mutations at the D816 position are found in the vast majorityof mastocytosis cases (90-98%), with the most common mutations beingD816V and D816H, and D816Y. The D816V mutation is found in theactivation loop of the kinase domain, and leads to constitutiveactivation of KIT kinase.

The compounds described herein may also be useful to treat GIST.Complete surgical resection remains the principal treatment of choicefor patients with a primary GIST. Surgery is effective in approximately50% of patients with GIST; of the remaining patients, tumor recurrenceis frequent. Primary treatment with a KIT inhibitor such as imatinib hasalso been shown to be sufficient for initial treatment. However,resistance to imatinib occurs within months through somatic mutation.These secondary imatinib resistant mutations are most frequently locatedon Exon 11, 13, 14, 17 or 18. Sunitinib is the standard of care secondline treatment for most imatinib resistant tumors and is effective forthose containing mutations in exons 11, 13 and 14. However, secondaryKIT mutations in exons 17 and 18 are resistant to sunitinib treatmentand furthermore, tumors containing tertiary resistance mutations in exon17 and 18 emerge several months after sunitinib treatment. Regorafenibhas shown promising results in a phase 3 clinical trial of imatinib,sunitinib resistant GISTs with activity against several but not all exon17 and 18 mutations, of which D816 is one. Thus, there is a need fortherapeutic agents to treat GIST patients with exon 17 mutations notaddressed by regorafenib.

In addition to the use of the compounds described herein as singleagents in the refractory GIST setting, the use of combinations ofimatinib, sunitinib and/or regorafenib with the compounds disclosedherein may allow for the prevention of emergence of resistance to exon17 mutations.

There is a subset of GIST patients with a D842V mutation in PDGFRα; thissubgroup of GIST patients can be stratified by identifying thismutation. This subset of patients is refractory to all tyrosine kinaseinhibitors currently available. The compounds described herein, due totheir activity against PDGFRα D842V, can be useful in treating thesepatients.

The compounds described herein may also be useful in treating AML. AMLpatients harbor KIT mutations as well, with the majority of thesemutations at the D816 position.

In addition, mutations in KIT have been linked to Ewing's sarcoma, DLBCL(diffuse large B cell lymphoma), dysgerminoma, MDS (myelodysplasticsyndrome), NKTCL (nasal NK/T-cell lymphoma), CMML (chronicmyelomonocytic leukemia), and brain cancers.

The compounds disclosed herein may be used to treat conditionsassociated with the KIT mutations in Exon 9, Exon 11, Exon 13, Exon 14,Exon 17 and/or Exon 18. They may also be used to treat conditionsassociated with wild-type KIT. The compounds described herein may beused as single agents to treat the conditions described herein, or theymay be used in combination with other therapeutic agents, including,without limitation, imatinib, sunitinib and regorafenib. Other agentsinclude the compounds described in WO 2014/039714 and WO 2014/100620.

Compounds described herein can be active against one or more KITmutations in Exon 17 (e.g., D816V, D816Y, D816F, D816K, D816H, D816A,D816G, D820A, D820E, D820G, N822K, N822H, Y823D, and A829P), and muchless active against wild-type KIT. These compounds can be administeredin combination with an agent that is (a) active against other activatingmutations of KIT, such as Exon 9 and 11 mutations, but (b) not activeagainst the Exon 17 mutations. Such agents include imatinib, sunitinib,and regorafenib. The combination of the compound and the agent will thusinhibit Exon 17 mutant KIT, as well as inhibiting Exon 9/11 mutant KIT.The compound and agent can be co-administered, or administered in analternating regimen. That is, the Exon 17 mutant KIT inhibitor can beadministered alone for a period of time; then the Exon 9/11 mutant KITinhibitor can be administered alone for a period of time following. Thiscycle may then be repeated. It is believed that such a regimen couldslow the development of resistance to the Exon 17 mutant KIT inhibitorand/or the Exon 9/11 mutant KIT inhibitor.

In addition, compounds described herein that can be selective for Exon17 KIT mutations can be administered with agents that are active againstExon 9/11 mutations, in combination with a third agent that coversmutations that are missed with the two-way combo. The combination of thethree agents could inhibit a spectrum of KIT mutations, as well aswild-type KIT in some instances. The agents could be administeredsimultaneously, or in an alternating regimen. They can be administeredone at a time, or two agents can be administered together for a periodof time; then the third agent can be administered alone for a followingperiod of time. It is believed that such a regimen could slow thedevelopment of resistance to the mutant KIT inhibitors.

Pharmaceutical Compositions

While it is possible for a compound disclosed herein to be administeredalone, it is preferable to administer the compound as a pharmaceuticalformulation, where the compound is combined with one or morepharmaceutically acceptable excipients or carriers. The compoundsdisclosed herein may be formulated for administration in any convenientway for use in human or veterinary medicine. In certain embodiments, thecompound included in the pharmaceutical preparation may be activeitself, or may be a prodrug, e.g., capable of being converted to anactive compound in a physiological setting.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Examples of pharmaceutically acceptable carriers include: (1) sugars,such as lactose, glucose and sucrose; (2) starches, such as corn starchand potato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21)cyclodextrins such as Captisol®; and (22) other non-toxic compatiblesubstances employed in pharmaceutical formulations.

Examples of pharmaceutically acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders,granules and the like) can include one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders,such as, for example, carboxymethylcellulose, alginates, gelatin,polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents.

Liquid dosage forms can include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredient, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Ointments, pastes, creams and gels may contain, in addition to an activecompound, excipients, such as animal and vegetable fats, oils, waxes,paraffins, starch, tragacanth, cellulose derivatives, polyethyleneglycols, silicones, bentonites, silicic acid, talc and zinc oxide, ormixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays can additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will vary depending upon thehost being treated, the particular mode of administration. The amount ofactive ingredient that can be combined with a carrier material toproduce a single dosage form will generally be that amount of thecompound which produces a therapeutic effect.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

When the compounds disclosed herein are administered as pharmaceuticals,to humans and animals, they can be given per se or as a pharmaceuticalcomposition containing, for example, 0.1 to 99.5% (more preferably, 0.5to 90%) of active ingredient in combination with a pharmaceuticallyacceptable carrier.

The formulations can be administered topically, orally, transdermally,rectally, vaginally, parentally, intranasally, intrapulmonary,intraocularly, intravenously, intramuscularly, intraarterially,intrathecally, intracapsularly, intradermally, intraperitoneally,subcutaneously, subcuticularly, or by inhalation.

Dosages

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient that is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound disclosed hereinemployed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient will range from about 0.0001 to about 100 mg perkilogram of body weight per day. If desired, the effective daily dose ofthe active compound may be administered as two, three, four, five, sixor more sub-doses administered separately at appropriate intervalsthroughout the day, optionally, in unit dosage forms. In someembodiments, the dose for humans will be 100-1000 mg, or 400-800 mg,administered twice daily; or 400-1000 mg, administered once daily.

Examples

The following examples are intended to be illustrative, and are notmeant in any way to be limiting.

The below Schemes are meant to provide general guidance in connectionwith preparing the compounds of the invention. One skilled in the artwould understand that the preparations shown in the Schemes can bemodified or optimized using general knowledge of organic chemistry toprepare various compounds of the invention.

Scheme 1 schematically depicts synthetic protocol 1. Triazine (B) can bereacted with amine (A, Z is aryl or heteroaryl) under nucleophilicaromatic substitution reaction conditions using an amine base such asdiisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solventsuch as dioxane to provide the amine-substituted triazine (C). Theamine-substituted triazine (C) can be substituted with piperazine (D, Xand Y are —CH—) under nucleophilic aromatic substitution reactionconditions using an amine base such as diisopropylethylamine (DIPEA) ortriethylamine (TEA) in a polar solvent such as dioxane to provide thepiperazine-substituted triazine (E). Piperazine-substituted heteroaryl(E) can be coupled to the organozinc bromide (F) using Negishi couplingconditions to provide the substituted triazine (G). As shown below,Compound 186 was prepared using synthetic protocol 1.

Synthesis ofN-(1-((S)-morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-4-(4-(5-((R)-1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-amine(Compound 186)

Step 1: Synthesis of (S)-tert-butyl2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate

To a solution of (S)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate (3.0 g, 13.8 mmol) andtriethylamine (4.2 g, 41.4 mmol) in dichloromethane (80 mL) at 0° C. wasdropwise added mesyl chloride (1.9 g, 16.5 mmol). The reaction mixturewas stirred at 0° C. for 2 hour, and then diluted with dichloromethane(100 mL). The organic layers were washed with water (100 mL) and brine(100 mL), dried over sodium sulfate, filtered and concentrated to afford(S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate asa purple oil (4.0 g, 98%), which was directly used in the next stepwithout further purification. MS (ES+) C₁₁H₂₁NO₆S requires: 295. found:240 [M+H−56]⁺.

Step 2: Synthesis of (S)-tert-butyl2-((4-nitro-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

To a solution of (S)-tert-butyl2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate (2.8 g, 9.5 mmol)and 4-nitro-1H-pyrazole (715 mg, 6.3 mmol) in acetonitrile (100 mL) wasadded cesium carbonate (6.2 g, 19.0 mmol). The reaction mixture wasstirred at 55° C. overnight and then concentrated. The residue wasdissolved in ethyl acetate (100 mL), washed with water (50 mL), driedover sodium sulfate, filtered and concentrated. The crude sample waspurified by silica gel chromatography, eluting with petroleumether:ethyl acetate=8:1, to afford (S)-tert-butyl2-((4-nitro-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate as a yellowoil (2.12 g, 71%). MS (ES+) C₁₃H₂₀N₄O₅ requires: 312. found: 257[M+H−56]⁺.

Step 3: Synthesis of (S)-tert-butyl2-((4-amino-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

To a solution of (S)-tert-butyl2-((4-nitro-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (3.2 g, 10.2mmol) in methanol (100 mL) was added Pd/C (600 mg). The mixture wasstirred under 1 atm H₂ at room temperature overnight, and then filtratedthrough a pad of celite. The filtrate was concentrated to afford(S)-tert-butyl2-((4-amino-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate. MS (ES+)C₁₃H₂₂N₄O₃ requires: 282. found: 283 [M+H]⁺.

Step 4: Synthesis of (S)-tert-butyl2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

To a solution of 2,4-dichloro-1,3,5-triazine (1.8 g, 6.4 mmol) indioxane (20 mL) was added diisopropylethylamine (4 mL), followed by theaddition of (S)-tert-butyl2-((4-amino-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (1.2 g, 7.2mmol). The reaction mixture was stirred at 110° C. for 1 hour, and LCMS(liquid chromatography-mass spectrometry) showed the reaction wascompleted. The solvents were removed under reduced pressure, and theresidue was purified by silica gel chromatography, eluting withpetroleum ether:ethyl acetate=5:1, to afford (S)-tert-butyl2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylateas a yellow solid (1.8 g, 70%). MS (ES+) C₁₆H₂₂ClN₇O₃ requires: 395,396. found: 396, 397 [M+H]⁺.

Step 5: Synthesis of 5-bromo-2-(piperazin-1-yl)pyrimidine HCl Salt

A solution of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5 g, 14.6 mmol) in 4M HCl-dioxane (50 mL) was stirred at room temperature for 1 hour. Thereaction mixture was concentrated to give5-bromo-2-(piperazin-1-yl)pyrimidine HCl salt (crude, 3.3 g, 94%) as awhite solid. MS (ES+) C₈H₁₁BrN₄ requires: 242, 244. found: 243, 245[M+H]⁺.

Step 6: Synthesis of (S)-tert-butyl2-((4-(4-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

To a solution of (S)-tert-butyl2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(1.8 g, 4.5 mmol) in dioxane (50 mL) was added diisopropylethylamine (4mL) and 5-bromo-2-(piperazin-1-yl)pyrimidine (1.3 g, 5.5 mmol). Thereaction mixture was stirred at room temperature for 2 hours. Thesolvents were removed, and the residue was washed with methanol (10 mL)to afford (S)-tert-butyl2-((4-(4-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)-morpholine-4-carboxylateas a white solid (2.4 g, 89%), which was directly used in the next stepwithout further purification. MS (ES+) C₂₄H₃₂BrN₁₁O₃ requires: 601, 603.found: 602, 604 [M+H]⁺.

Step 7: Synthesis of (2S)-tert-butyl2-((4-(4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

To a solution of (S)-tert-butyl2-((4-(4-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(100 mg, 0.17 mmol) and Pd(Amphos)Cl₂ (11.7 mg, 0.17 mmol) in THF (2 mL,dried) was dropwise added a solution of (1-phenylethyl)zinc(II) bromidein THF (7.0 mL, 0.5 M, 3.4 mmol). The reaction mixture was stirred at70° C. for 1 hour under N₂, then cooled to room temperature and dilutedwith ethyl acetate (50 mL). After filtration, the filtrate wasconcentrated to afford (2S)-tert-butyl2-((4-(4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylateas a white solid (130 mg, crude), which was directly used in the nextstep without further purification. MS (ES+) C₃₂H₄₁N₁₁O₃ requires: 627.found: 628 [M+H]⁺.

Step 8: Synthesis ofN-(1-((S)-morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-4-(4-(5-((R)-1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-amine

To a solution of (2S)-tert-butyl2-((4-(4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(130 mg, crude) in dichloromethane (6 mL) was dropwise addedtrifluoroacetic acid (2 mL). The reaction mixture was stirred at roomtemperature for 0.5 hour and then concentrated. The residue was purifiedby Prep-HPLC to provideN-(1-((S)-morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-4-(4-(5-(1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-amineas a white solid, which was then separated by Chiral-HPLC to affordN-(1-((S)-morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-4-(4-(5-((R)-1-phenylethyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-amineas a white solid (15.4 mg, 17%).

Scheme 2 schematically depicts synthetic protocol 2. Triazine (B) can bereacted with amine (A, Z is aryl or heteroaryl) under nucleophilicaromatic substitution reaction conditions using an amine base such asdiisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solventsuch as dioxane to provide the amine-substituted triazine (C). Theamine-substituted triazine (C) can be substituted with piperazine (D, Xand Y are —CH—, A is aryl, and L is C₁₋₆ alkyl, cycloalkyl, C₁₋₆haloalkyl, or sulfur) under nucleophilic aromatic substitution reactionconditions using an amine base such as diisopropylethylamine (DIPEA) ortriethylamine (TEA) in a polar solvent such as dioxane to provide thepiperazine-substituted triazine (E). As shown below, Compound 165 wasprepared using synthetic protocol 2.

Synthesis of(R)-1-(4-((4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-yl)amino)benzyl)piperidin-3-ol(Compound 165)

Step 1: Synthesis of (R)-1-(4-nitrophenyl)piperidin-3-ol

4-Fluoronitrobenze (1.5 g, 10.6 mmole), (R)-piperidin-3-ol HCl (1.76 g,12.8 mmole) and potassium carbonate (4.41 g, 31.9 mmole) were combinedin 10 mL DMF and heated to 60° C. overnight. The reaction mixture wascooled to room temperature and poured into ˜75 mL water; the suspensionwas stirred at room temperature for 30 minutes. The mixture was thenfiltered, washed with water and suction dried to give 2.25 g (95%) of(R)-1-(4-nitrophenyl)piperidin-3-ol as a yellow solid.

Step 2: Synthesis of (R)-1-(4-aminophenyl)piperidin-3-ol

To a solution of (R)-1-(4-nitrophenyl)piperidin-3-ol was added Pd/C. Themixture was stirred under 1 atm H₂ at room temperature overnight, andthen filtrated through a pad of Celite. The filtrate was concentrated toafford (R)-1-(4-aminophenyl)piperidin-3-ol.

Step 3: Synthesis of(R)-1-(4-((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)piperidin-3-ol

To a solution of 2,4-dichloro-1,3,5-triazine in dioxane was addeddiisopropylethylamine, followed by the addition of(R)-1-(4-aminophenyl)piperidin-3-ol. The reaction mixture was stirred at110° C. for 1 hour, and LCMS (liquid chromatography-mass spectrometry)showed the reaction was completed. The solvents were removed underreduced pressure, and the residue was purified by silica gelchromatography, eluting with petroleum ether:ethyl acetate=5:1, toafford(R)-1-(4-((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)piperidin-3-ol.

Step 4: Synthesis of(R)-1-(4-((4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-yl)amino)benzyl)piperidin-3-ol

To a solution of(R)-1-(4-((4-chloro-1,3,5-triazin-2-yl)amino)phenyl)piperidin-3-ol indioxane was added diisopropylethylamine5-benzyl-2-(piperazin-1-yl)pyrimidine. The reaction mixture was stirredat room temperature for 2 hours. The solvents were removed, and theresidue was washed with methanol (10 mL) to afford(R)-1-(4-((4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-yl)amino)benzyl)piperidin-3-ol(Compound 165).

Scheme 3 schematically depicts synthetic protocol 3. Triazine (B) can bereacted with piperizine (A, X and Y are —CH—, A is aryl, and L is C₁₋₆alkyl, cycloalkyl, C₁₋₆haloalkyl, or sulfur) under nucleophilic aromaticsubstitution reaction conditions using an amine base such asdiisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solventsuch as dioxane to provide the piperizine-substituted triazine (C). Thepiperizine-substituted triazine (C) can be substituted with amine (D, Zis aryl or heteroaryl) under nucleophilic aromatic substitution reactionconditions using an amine base such as diisopropylethylamine (DIPEA) ortriethylamine (TEA) in a polar solvent such as dioxane to provide thepiperazine-substituted triazine (E). As shown below, Compound 64 wasprepared using synthetic protocol 3.

Synthesis of1-(4-(4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)ethane-1,2-diol

Step 1: Synthesis of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzenesulfonate

To a solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (5.28 g, 40.0mmol), triethyl amine (12.12 g, 120.0 mmol) and 4-dimethylaminopyridine(500 mg, 4.0 mmol) in dichloromethane (200 mL) was added tosyl chloride(15.2 g, 80.0 mmol). The reaction mixture was stirred at RT overnight,then quenched with water (200 mL) and extracted with ethyl acetate. Theorganic layers were separated, combined, washed with water (200 mL) andbrine (200 mL), dried over sodium sulfate, filtered, and concentrated.The residue was purified by silica gel chromatography, eluting withethyl acetate/petroleum ether=1/8, to afford(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (6.1 g,yield 53%), MS (ES+) C₁₃H₁₈O₅S requires: 286. found: 287 [M+H]⁺.

Step 2: Synthesis of1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-nitro-1H-pyrazole

A solution of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzenesulfonate (1.57 g, 5.5 mmol), 4-nitro-1H-pyrazole (0.57g, 5.0 mmol) and cesium carbonate (4.89 g, 15.0 mmol) in acetonitrile(30 mL) was stirred at 70° C. under N₂ overnight. The reaction mixturewas filtered, and the resulting filtrate was concentrated. The residuewas diluted with ethyl acetate (50 mL), washed with water (50 mL×2) andbrine (50 mL), dried over sodium sulfate, filtered, and concentrated toafford 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-nitro-1H-pyrazole(1.01 g, crude), which was directly used in the next step withoutfurther purification. MS (ES+) C₉H₁₃N₃O₄ requires: 227. found: 228[M+H]⁺.

Step 3: Synthesis of1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-amine

A mixture of1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-4-nitro-1H-pyrazole (2.0 g,9.5 mmol) and Pd/C (400 mg) in methanol (40 mL) was stirred at RT underH₂ overnight. LCMS showed the reaction was completed. The reactionmixture was filtered through a pad of celite, and the filtrate wasconcentrated to give1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-amine (1.7 g,crude) as a purple oil, which was directly used in the next step withoutfurther purification. MS (ES+) C₉H₁₅N₃O₂ requires: 197. found: 198[M+H]⁺.

Step 4: Synthesis of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate

To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1,4-dioxane (500mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixturewas stirred under reflux for 1.5 h. The mixture was diluted with water(500 mL) and extracted with diethyl ether (1000 mL*2). The combinedorganic layers were dried over sodium sulfate, filtered andconcentrated. The residue was purified with silica gel chromatography(elute:hexane:ethyl acetate=8:1 to 4:1) to give tert-butyl4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate (70.5 g, 80%) as awhite solid. MS (ES+) C₁₃H₁₉BrN₄O₂ requires: 342. found: 243 [M+H−100]⁺.

Step 5: Synthesis of Benzylzinc(II) Bromide

To a suspension mixture of zinc powder (active, 65 g, 1.0 mol) in dryTHF (200 mL) was dropwise added 1,2-dibromoethane (3.5 mL, 40 mmol) at65° C. under nitrogen atmosphere, followed by the addition ofchlorotrimethylsilane (87 mg, 80 mmol). The mixture was then stirred at60° C. for another 1 h. Subsequently, (bromomethyl)benzene (60 mL, 500mmol) was dropwise added, and the suspension was stirred at 60° C. foranother 1 h. The reaction mixture was directly used in the next step.

Step 6: Synthesis of tert-butyl4-(5-benzylpyrimidin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (12.0 g, 35.0 mmol)and tetrakis(triphenylphosphine)palladium (2.0 g, 1.7 mmol) in THF (200mL, dry) was added dropwise a solution of benzylzinc(II) bromide in THF(140 mL, 0.5 M, 70 mmol). The reaction mixture was stirred at 70° C. for4 h under N₂, cooled to RT, then diluted with ethyl acetate (300 mL),filtered and concentrated. The residue was purified by silica gelchromatography, eluting with ethyl acetate/petroleum ether=1/20˜1/10, togive -butyl 4-(5-benzylpyrimidin-2-yl)piperazine-1-carboxylate (7.5 g,yield 60%) as a white solid, MS (ES+) C₂₀H₂₆N₄O₂ requires: 354. found:355 [M+H]⁺.

Step 7: Synthesis of 5-benzyl-2-(piperazin-1-yl)pyrimidine HydrogenChloride Salt

To a solution of tert-butyl4-(5-benzylpyrimidin-2-yl)piperazine-1-carboxylate (8.0 g, 23.0 mmol) in1,4-dioxane (30 mL) was dropwise added a solution of 4 M HCl-dioxane (20mL, 80 mmol). The reaction mixture was stirred at RT overnight, and thenconcentrated to give 5-benzyl-2-(piperazin-1-yl)pyrimidine HCl salt(10.2 g, crude) as a yellow solid, MS (ES+) C₁₅H₁₈N₄ requires: 254.found: 255 [M+H−100]⁺.

Step 8: Synthesis of2-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-4-chloro-1,3,5-triazine

A solution of 2,4-dichloro-1,3,5-triazine (315 mg, 2.1 mmol),5-benzyl-2-(piperazin-1-yl)pyrimidine (510 mg, 2.0 mmol) and Hunig'sbase (540 mg, 4.2 mmol) in 1,4-dioxane (6 mL) was stirred at 60° C. for1 h. LCMS showed the reaction was completed. The reaction mixture wascooled to RT, diluted by water (60 mL), and extracted with ethyl acetate(40 mL×3). The organic layers were combined, washed with water andbrine, dried over sodium sulfate, filtered and concentrated to give1-(2,2-dimethyl-1,3-dioxolan-4-yl)-1H-pyrazol-4-amine (280 mg, crude) asa yellow solid, which was directly used in the next step without furtherpurification. MS (ES+) C₁₈H₁₈ClN₇ requires: 367. found: 368 [M+H]⁺.

Step 9: Synthesis of4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine

A solution of2-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-4-chloro-1,3,5-triazine(110 mg, 0.3 mmol),1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-amine (90 mg,0.45 mmol) and Hunig's base (80 mg, 0.6 mmol) in 1,4-dioxane (4 mL) wasstirred at 60° C. for 5 h. LCMS showed the reaction was completed. Thereaction mixture was cooled to RT and diluted with ethyl acetate (40mL). The organic phase was washed with water (40 mL) and brine (20 mL),dried over sodium sulfate, filtered and concentrated to give4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine(200 mg, crude) as a yellow solid, which was directly used in the nextstep without further purification. MS (ES+) C₂₆H₃₀N₁₀O₂ requires: 528.found: 529 [M+H]⁺.

Step 10: Synthesis of3-(4-(4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)propane-1,2-diol

A solution of4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine(200 mg, 0.3 mmol), and p-TSA (40 mg, 0.2 mmol) in dichloroethane (2.5mL) was stirred at 80° C. under N₂ overnight. LCMS showed the reactionwas completed. The reaction mixture was cooled to RT and diluted withethyl acetate (40 mL). The organic phase was washed with water (30 mL)and brine (30 mL), dried over sodium sulfate, filtered and concentrated.The residue was purified by Prep-HPLC to give3-(4-(4-(4-(5-benzylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)propane-1,2-diol(13.8 mg, yield 7%) as a white solid. MS (ES+) C₂₄H₂₈N₁₀O₂ requires:488. found: 489 [M+H]⁺.

Scheme 4 schematically depicts synthetic protocol 4. The piperazinecarbonyl derivative, e.g., carbamoyl, (A, X and Y are each —CH—) can becoupled to the Grignard bromide (2, Ring A is aryl), to provide theprotected di-substituted carbonyl (C, X¹ is CH₂, S, NH, or O). When X¹is O, i.e., a carbonyl, the carbonyl can be further reacted with anorganometallic reagent such as trialkylaluminum, e.g.,trimethylaluminum, which can also deprotect the piperazine nitrogen toprovide the dialkyl compound (C′, alkyl is C₁₋₆ alkyl). Removal of theprotecting group (P) from the piperazine ring of (C) can be carried outusing strong acids such as 4M hydrochloric acid (HCl) in dioxane ortrifluoroacetic acid (TFA) in a polar solvent such as methanol ordichloromethane (DCM) to afford amine (D). Triazine (E) can besubstituted with amine (C′) or (D) under nucleophilic aromaticsubstitution reaction conditions using an amine base such asdiisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solventsuch as dioxane to provide the piperazine-substituted triazine (F) or(F′). Reduction of —C(═X¹)—, wherein X¹ is CH₂, S, NH, or O, e.g.,carbonyl, of (F) can be performed using a reducing agent such as sodiumborohydride to provide —C—(XH)—, e.g., the alcohol (G). As shown below,Compound 189 was prepared using synthetic protocol 4.

Synthesis of (S) (2 (4 (4 (1(morpholin-2-ylmethyl)-1H-pyrazol-4-ylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanol(Compound 189)

Step 1: Synthesis of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (7.9 g, 42.5 mmol)and diisopropylethylamine (13.69 g, 106.1 mmol) in dichloromethane (80mL) was added ethyl 2-chloropyrimidine-5-carboxylate (7.9 g, 42.5 mmoL),and the reaction mixture was stirred at room temperature for 3 hours.LCMS showed the reaction was completed. The reaction mixture wasdirectly concentrated to afford ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (17 g,crude), which was directly used in the next step without furtherpurification. MS (ES+) C₁₆H₂₄N₄O₄ requires: 336. found: 237, 281[M−56+H]⁺.

Step 2: Synthesis of2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid

To a solution of ethyl2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (17 g,crude) in THF/methanol/H₂O (300 mL) was added sodium hydroxide (4.3 g,107.5 mmol), and the reaction mixture was stirred at 70 0° C. for 2hours. LCMS showed the reaction was completed. The reaction mixture wasbrought to pH≈5-6 with 1 M HCl, and then filtered. The solid wascollected and dried to give2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid asa white solid (16 g, 96%), which was directly used in the next stepwithout further purification. MS (ES+) C₁₄H₂₀N₄O₄ requires: 308. found:253 [M−56+H]⁺.

Step 3: Synthesis of tert-butyl4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1

To a suspension of2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid(13.8 g, 44.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (12.8g, 67.2 mmol) and hydroxybenzotriazole (7.2 g, 53.7 mmol) indichloromethane (200 mL) was added triethylamine (25 mL, 179.2 mmol).The mixture was stirred at room temperature for 1 hour, and thenN,O-dimethylhydroxylamine (5 g, 53.7 mmol) was added. The reactionmixture was stirred for another 3 hours. LCMS showed the reaction wascompleted. The reaction mixture was directly washed with water (100 mL),and the organic layer was dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(petroleum ether:ethyl acetate=1:1) to give tert-butyl4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate(11.2 g, 67%) as a white solid. MS (ES+) C₁₆H₂₅N₅O₄ requires: 351.found: 296 [M−56+H]⁺.

Step 4: Synthesis of tert-butyl4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate(2.6 g, 7.4 mmol) in dry THF (30 mL) was added benzylmagnesium bromide(1 M in THF, 29.6 mL) at 0° C. under N₂, and the mixture was stirred atroom temperature for 3 hours. LCMS showed the reaction was completed.The reaction mixture was quenched with 1 M HCl and extracted with ethylacetate. The organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated. The residue was purified bysilica gel chromatography (petroleum ether:ethyl acetate=5:1) to gettert-butyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (2 g,73%) as a yellow solid. MS (ES+) C₂₀H₂₄N₄O₃ requires: 368. found: 313[M−56+H]⁺.

Step 5: Synthesis of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanoneHCl salt

To a solution of tert-butyl4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (1 g, 2.7 mmol) indioxane (20 mL) was added 4 M HCl-dioxane (20 mL), and the reactionmixture was stirred at room temperature overnight. LCMS showed thereaction was completed. The mixture was directly concentrated to givephenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone HCl salt as ayellowish solid (0.95 g, 90%). MS (ES+) C₁₅H₁₆N₄O requires: 268. found:269 [M+H]⁺.

Step 6: Synthesis of (S)-tert-butyl2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

The synthesis of (S)-tert-butyl2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(7) was carried out following the synthetic procedure of Example 1.)

To a mixture of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone HClsalt (141.6 mg, 0.38 mmol) and (S)-tert-butyl2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(150 mg, 0.38 mmol) in dioxane (10 mL) was added diisopropylethylamine(1 mL), and the reaction was stirred at room temperature overnight. LCMSshowed the reaction was completed. The solvents were removed underreduced pressure, and the residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=1:1) to give(S)-tert-butyl2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(230 mg, 95%) as a yellowish solid. (MS (ES+) C₃₁H₃₇N₁₁O₄ requires: 627.found: 573 [M−56+H]⁺.

Step 7: Synthesis of (S)-tert-butyl2-((4-(4-(4-(5-(hydroxy(phenyl)methyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

To a solution of (S)-tert-butyl2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(80 mg, 0.127 mmol) in THF/methanol was added sodium borohydride (20 mg,0.51 mmol). The mixture was stirred at room temperature for 1 hour, andLCMS showed the reaction was completed. The solvents were removed togive (S)-tert-butyl2-((4-(4-(4-(5-(hydroxy(phenyl)methyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(80 mg, crude) as a yellowish solid. (MS (ES+) C₃₁H₃₉N₁₁O₄ requires:629. found: 630 [M+H]⁺.

Step 8: Synthesis of(S)-(2-(4-(4-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-ylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanol

To a solution of (S)-tert-butyl2-((4-(4-(4-(5-benzoylpyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(80 mg, 0.127 mmol, crude) in dioxane (4 mL) was added 4 M HCl-dioxane(4 mL), and the reaction was stirred at room temperature overnight. LCMSshowed the reaction was completed. The solvent was removed, and theresidue was purified by Prep-HPLC to provide the title compound(S)-(2-(4-(4-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-ylamino)-1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidin-5-yl)(phenyl)methanol(Compound 189) (24.0 mg, 18%) as a yellowish solid.

Scheme 5 schematically depicts synthetic protocol 5. The N-protectedheteroaryl-substituted piperazine (A, X and Y are each —CH—) can becoupled to an alcohol, thiol, or amine, (B, —Z—H is —OH, —SH, or —NH₂;Ring A is aryl) via a copper-mediated coupling reaction, e.g., such asthe Ullman reaction, to provide the protected heteroaryl-ether (C).Removal of the protecting group (P) from the piperazine ring can becarried out using strong acids such as 4M hydrochloric acid (HCl) indioxane or trifluoroacetic acid (TFA) in a polar solvent such asmethanol or dichloromethane (DCM) to afford amine (D). Triazine (E) canbe substituted with amine (D) under nucleophilic aromatic substitutionreaction conditions using an amine base such as diisopropylethylamine(DIPEA) or triethylamine (TEA) in a polar solvent such as dioxane toprovide the piperazine-substituted triazine (F). As shown below,Compound 203 was prepared using synthetic protocol 5.

Synthesis of(S)-4-(4-(5-(2-fluorophenoxy)pyrimidin-2-yl)piperazin-1-yl)-N-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine(Compound 203)

Step 1: Synthesis of tert-butyl4-(5-(2-fluorophenoxy)pyrimidin-2-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (684 mg, 2.0 mmol),2-fluorophenol (1.1 g, 10.0 mmol), copper (650 mg, 10.0 mmol) and cesiumcarbonate (6.5 g, 20.0 mmol) in pyridine (15 mL) was heated at 120 0° C.in a sealed tube overnight. The reaction mixture was diluted with ethylacetate (200 mL) and then filtered. The filtrate was concentrated, andthe residue was purified by silica gel chromatography (petroleumether:ethyl acetate 20:1) to give tert-butyl4-(5-(2-fluorophenoxy)pyrimidin-2-yl)piperazine-1-carboxylate (50 mg,6%) as a yellow solid. MS (ES+) C₁₉H₂₃FN₄O₃ requires: 374. found: 397[M+Na]⁺.

Step 2: Synthesis of 5-(2-fluorophenoxy)-2-(piperazin-1-yl)pyrimidineHCl Salt

To a solution of tert-butyl4-(5-(2-fluorophenoxy)pyrimidin-2-yl)piperazine-1-carboxylate (50 mg,0.13 mmol) in dioxane (3 mL) was added 4 M HCl/dioxane (3 mL). Thereaction mixture was stirred at room temperature overnight and thenconcentrated to dryness. The residue (50 mg, yellow solid) was directlyused in the next reaction.

Step 3: Synthesis of (S)-tert-butyl2-((4-(4-(4-(5-(2-fluorophenoxy)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

The synthesis of (S)-tert-butyl2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(5) was carried out following the synthetic procedure of Example 1.

A mixture of 5-(2-fluorophenoxy)-2-(piperazin-1-yl)pyrimidine HCl salt(27 mg, 0.1 mmol), (S)-tert-butyl2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)-morpholine-4-carboxylate(40 mg, 0.1 mmol) and diisopropylethylamine (25 mg, 2.0 mmol) in dioxane(2 mL) was stirred at room temperature for 2 hours. The reaction mixturewas directly evaporated and used in the next step.

Step 4: Synthesis of(S)-4-(4-(5-(2-fluorophenoxy)pyrimidin-2-yl)piperazin-1-yl)-N-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine

The above crude sample was dissolved in dichloromethane (10 mL),followed by the addition of trifluoroacetic acid (4 mL). The mixture wasstirred at room temperature overnight. The solvent was removed, and theresidue was purified by Prep-HPLC to(S)-4-(4-(5-(2-fluorophenoxy)-pyrimidin-2-yl)piperazin-1-yl)-N-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine(4.3 mg) as a white solid.

Scheme 6 schematically depicts synthetic protocol 6. The N-protectedheteroaryl-substituted piperazine (A, X and Y are each —CH—) can becoupled to alkyne (B, Ring A is cycloalkyl) via a palladium-mediatedcoupling reaction, e.g., Sonogashira coupling, to provide the protectedheteroaryl-alkyne (C). Removal of the protecting group (P) from thepiperazine ring can be carried out using strong acids such as 4Mhydrochloric acid (HCl) in dioxane or trifluoroacetic acid (TFA) in apolar solvent such as methanol or dichloromethane (DCM) to afford amine(D). Triazine (E) can be substituted with amine (D) under nucleophilicaromatic substitution reaction conditions using an amine base such asdiisopropylethylamine (DIPEA) or triethylamine (TEA) in a polar solventsuch as dioxane to provide the piperazine-substituted triazine (F). Asshown below, Compound 63 was prepared using synthetic protocol 6.

Synthesis of(S)-4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-N-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine(Compound 63)

Step 1: Synthesis of tert-butyl4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazine-1-carboxylate

In a sealed tube, the mixture of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (1.0 g, 2.9 mmol),ethynylcyclopropane (482 mg, 7.3 mmol),tetrakis(triphenyl-phosphine)palladium (335 mg, 0.29 mmol) and copper(I)iodide (28 mg, 0.15 mmol) in diethylamine (10 mL) and dimethyl sulfoxide(10 mL) was stirred at 100° C. for 3 hours under nitrogen atmosphere.The mixture was then diluted with ethyl acetate (100 mL) and washed withwater and brine. The organic phase was dried over sodium sulfate,filtered and concentrated. The residue was purified by silica gelchromatography eluting with petroleum ether:ethyl acetate=15:1 to affordtert-butyl4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazine-1-carboxylate (930mg, 98%) as a yellow solid. MS (ES+) C₁₈H₂₄N₄O₂ requires: 328. found:329 [M+H]⁺.

Step 2: Synthesis of 5-(cyclopropylethynyl)-2-(piperazin-1-yl)pyrimidineHCl salt

To a solution of tert-butyl4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazine-1-carboxylate (150mg, 0.46 mmol) in dioxane (3 mL) was added 4 M HCl-dioxane (3 mL), andthe reaction mixture was stirred room temperature for 1 hour. LCMSshowed the reaction was completed. The reaction mixture was concentratedto afford 5-(cyclopropylethynyl)-2-(piperazin-1-yl)pyrimidine HCl saltas a white solid (100 mg, crude), which was directly used in the nextstep without further purification. MS (ES+) C₁₃H₁₆N₄ requires: 228.found: 229 [M+H]⁺.

Step 3: Synthesis of (S)-tert-butyl2-((4-(4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate

The synthesis of (S)-tert-butyl2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate5 was performed as shown elsewhere herein.

To a solution of 5-(cyclopropylethynyl)-2-(piperazin-1-yl)pyrimidine HClsalt (172 mg, 0.44 mmol) and (S)-tert-butyl2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylatewas added diisopropylethylamine (169 mg, 1.311 mmol), and the reactionmixture was stirred at room temperature. LCMS showed the reaction wascompleted. The mixture was concentrated, and the residue was purified bysilica gel chromatography, eluting with petroleum ether: ethylacetate=1:2, to afford (S)-tert-butyl2-((4-(4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(240 mg, 94%) as a yellowish solid. MS (ES+): C₂₉H₃₇N₁₁O₃ requires: 587.found: 588 [M+H]⁺.

Step 4: Synthesis of(S)-4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-N-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine

To a solution of (S)-tert-butyl2-((4-(4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate(30 mg, 0.05 mmol) in dichloromethane (2 mL) was dropwise addedtrifluoroacetic acid (1 mL). The reaction mixture was stirred at roomtemperature for 0.5 hour and concentrated. The residue was purified byPrep-HPLC to afford(S)-4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-N-(1-(morpholin-2-ylmethyl)-1H-pyrazol-4-yl)-1,3,5-triazin-2-amine(14 mg, 57%) as a white solid.

Preparation of Common Intermediates Synthesis of5-(2-phenylpropan-2-yl)-2-(piperazin-1-yl)pyrimidine

In a sealed tube, the mixture of tert-butyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (500 mg, 1.36 mmol) and trimethylaluminum (2 Min toluene, 2.7 mL) in dry toluene (10 mL) was stirred at 100 0° C.overnight. LCMS showed the reaction was completed. The reaction mixturewas cooled to RT, quenched with ice-water and extracted with ethylacetate. The organic layer was washed with water and brine, dried oversodium sulfate, filtered and concentrated. The residue was purified byPrep-HPLC to get 5-(2-phenylpropan-2-yl)-2-(piperazin-1-yl)pyrimidine(40 mg, 7%) as a yellowish solid. MS (ES+) C₁₇H₂₂N₄ requires: 282.found: 283 [M+H]⁺.

Synthesis of 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol

A mixture of 4-nitro-1H-pyrazole (1.6 g, 13.9 mmol),1-chloro-2-methylpropan-2-ol (1.5 g, 13.9 mmol) and Cs₂CO₃ (9.1 g, 27.8mmol) in DMF (20 mL) was stirred at 80° C. for 5 h. The reaction mixturewas cooled to RT and diluted with EA (200 ml). The organic phase waswashed by water (50 mL) and brine (50 mL), dried over anhydrous sodiumsulfate and concentrated under reduced pressure to give2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol as a yellow oil (2.0 g,78%), which was used for the next step without further purification. MS(ES+) C₇H₁₁N₃O₃ requires: 185. found: 186 [M+H]⁺.

Synthesis of 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol

A stirred suspension mixture of2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (2.0 g, 10.8 mmol) and10% Pd/C (0.2 g, 0.1 w/w) in MeOH (20 mL) was exposed to 1 atm H₂ at RTovernight. The reaction mixture was filtered through a pad of celite.The filtrate was concentrated under reduced pressure to give1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol as a yellow oil (1.9 g,99%), which was used for the next step without further purification. MS(ES+) C₇H₁₃N₃O requires: 155. found: 156 [M+H]⁺.

Synthesis of 1-((4-bromophenyl)diazenyl)pyrrolidine

To a solution of 4-bromoaniline (1.7 g, 9.88 mmol) in conc. HCl (2 mL)was added a solution of NaNO₂ (682 mg, 9.88 mmol) in water (3 mL) at 0°C. The solution was stirred at 0° C. for 10 minutes, followed by theaddition of pyrrolidine (844 mg, 11.86 mmol) in KOH solution (1 mL, 1N). The resultant mixture was stirred at 0° C. for 0.5 h. The formedprecipitate was collected by filtration, washed with 1 mL of ethanol anddried to give the title compound as a yellow solid (1.5 g, yield 60%).MS (ES+) C₁₀H₁₂BrN₃ requires: 253, 255. found 254, 256 [M+H]⁺, purity:93%.

Synthesis of 3-(4-(pyrrolidin-1-yldiazenyl)phenyl)oxetan-3-ol

To a solution of 1-((4-bromophenyl)diazenyl)pyrrolidine (500 mg, 1.97mmol) in anhydrous THF (20 mL) was added n-BuLi (1.8 mL, 4.33 mmol)dropwise at −78° C. under N₂. The solution was stirred at −78° C. for 1h, followed by the addition of oxetan-3-one (326 mg, 4.53 mmol). Theresultant mixture was stirred at RT for 18 h. The reaction was quenchedby saturated aqueous NH₄Cl aq. (20 mL) and extracted with ethyl acetate(20 mL*3). The combined organic layers were concentrated under reducedpressure to give a residue, which was purified by silica gelchromatography (DCM:MeOH=20:1) to afford the title compound (500 mg,yield 97%) as a light yellow solid. MS (ES+) C₁₃H₁₇N₃O₂ requires: 247.found 248 [M+H]⁺, purity: 90%.

Synthesis of 3-(4-aminophenyl)oxetan-3-ol

To a solution of 3-(4-(pyrrolidin-1-yldiazenyl)phenyl)oxetan-3-ol (500mg, 2.02 mmol) in methanol (15 mL) was added Pd/C (10%, 250 mg) at RT.The reaction mixture was stirred under 1 atm H₂ atmosphere (balloon) at40° C. for 18 h. The mixture was filtered through a pad of Celite. Thefiltrate was concentrated to give a residue, which was purified byPrep-HPLC to afford the title compound (200 mg, yield 60%) as a whitesolid. MS (ES+) C₉H₁₁NO₂ requires: 165. found 166 [M+H]⁺, purity: 96%.

Synthesis of tert-butyl 1-(2-methylprop-1-enyl)-4-nitrobenzene

A mixture of 1-iodo-4-nitrobenzene (2.49 g, 10.0 mmol),4,4,5,5-tetramethyl-2-(2-methylprop-1-enyl)-1,3,2-dioxaborolane (1.82 g,10.0 mmol), sodium bicarbonate (2.52 g, 30.0 mmol) and[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (816 mg, 1.0 mmol) in dioxane/water (5:1, 60 mL) wasstirred at 90° C. for 20 h under N₂. LCMS and TLC monitored the reactionwas completed. The reaction mixture was cooled to RT and concentrated.The residue was dissolved in 100 mL of EtOAc, washed with water (150mL×3) and brine, dried over Na₂SO₄, filtered and concentrated undervacuo. The crude product was purified by silica gel column, eluting withPE:EA (6:1), to obtain the desired product (1.9 g, 100% yield) as ayellow oil, ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.17 (d, 2H, J=8.8 Hz), 7.35(d, 2H, J=8.8 Hz), 6.36 (s, 1H), 1.96 (d, 3H, J=0.4 Hz), 1.90 (d, 3H,J=0.4 Hz).

Synthesis of 2-methyl-1-(4-nitrophenyl)propane-1,2-diol

To a solution of N-methyl morpholine-N-oxide (1.5 g, 12.8 mmol) in 4.5mL of water was added a solution of tert-butyl1-(2-methylprop-1-enyl)-4-nitrobenzene (1.5 g, 8.5 mmol) inacetone/water (5:1, 36 mL), followed by the addition of a solution ofosmium tetraoxide in water (2 mL, 4%). This mixture was allowed to RTand stirred for 16 h. The reaction was quenched by sat. Na₂SO₃. aq (100mL) and extracted with EtOAc (50 mL×3). The combined organic layers werewashed with water and brine, dried over Na₂SO₄, filtered andconcentrated under vacuo. The crude product (1.7 g, yield 100%) wasobtained as a yellow foam, which was directly used into the next stepwithout further purification. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.20 (d, 2H,J=9.2 Hz), 7.57 (d, 2H, J=9.2 Hz), 4.63 (d, 1H, J=2.4 Hz), 2.69 (d, 1H,J=3.2 Hz), 2.03 (d, 1H, J=3.2 Hz), 1.19 (s, 3H), 1.08 (s, 3H).

Synthesis of 2,2,4,4-tetramethyl-5-(4-nitrophenyl)-1,3-dioxolane

A solution of 2-methyl-1-(4-nitrophenyl)propane-1,2-diol (1.5 g, 7.1mmol), 2,2-dimethoxypropane (1.45 g, 14.2 mmol) and TsOH (cat., 260 mg,1.5 mmol) in acetone (40 mL) was stirred at 30° C. for 16 h. Thereaction mixture was concentrated. The residue was purified by silicagel chromatography, eluting with PE:EA (8:1), to obtain the desiredproduct (1.5 g, 85% yield) as a white solid. ¹H-NMR (500 MHz, CDCl₃) δppm 8.23 (d, 2H, J=9.0 Hz), 7.57 (d, 2H, J=9.0 Hz), 4.93 (s, 1H), 1.59(s, 3H), 1.48 (s, 3H), 1.46 (s, 3H), 0.78 (s, 3H).

Synthesis of (R) and(S)-2,2,4,4-tetramethyl-5-(4-nitrophenyl)-1,3-dioxolane

The racemic material 2,2,4,4-tetramethyl-5-(4-nitrophenyl)-1,3-dioxolane(1.3 g) was separated by chiral HPLC to obtain peak 1 (630 mg, 100% ee)and peak 2 (610 mg, 99.6% ee).

Synthesis of (R)-4-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)aniline

A mixture of (R)-2,2,4,4-tetramethyl-5-(4-nitrophenyl)-1,3-dioxolane(200 mg, 0.797 mmol) and Pd/C (10%, 60 mg) in EtOAc/IPA (10 mL/10 mL)was stirred under 1 atm H₂ atmosphere (balloon) at RT for 16 h. Themixture was filtered through a pad of Celite. The filtrate wasconcentrated under reduced pressure to afford the desired product (180mg, 100%), which was directly used into the next step without furtherpurification.

Synthesis of 1-(4-nitrophenyl)ethane-1,2-diol

To a stirred solution of ethyl 2-(4-nitrophenyl)-2-oxoacetate (10.0 g,47.8 mmol) in ethanol (100 mL) was slowly added sodium borohydride (4.54g, 119.5 mmol) at 0° C. After the addition was completed, the reactionmixture was allowed to warm to RT and stirred for 12 h. The reaction wasquenched by acetone (10 mL) and concentrated. The residue was purifiedby silica gel column chromatography (dichloromethane/methanol=5/1) toafford the title compound (8.0 g, 87%) as a brown solid. MS (ES+)C₈H₉NO₄ requires: 183. found: 184 [M+H]⁺.

Synthesis of 2,2-dimethyl-4-(4-nitrophenyl)-1,3-dioxolane

A mixture of 1-(4-nitrophenyl)ethane-1,2-diol (7.0 g, 38.3 mmol),2,2-dimethoxypropane (16 g, 153.2 mmol) and 4-methylbenzenesulfonic acid(2.6 g, 15.32 mmol) in acetone (100 mL) was stirred at 25° C. for 12 h.The reaction mixture was concentrated and then dissolved in ethylacetate (300 mL). The organic layer was separated, washed by water (100mL) and brine (100 mL), dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel columnchromatography (petroleum ether/ethyl acetate=5/1) to afford the titlecompound (4.0 g, 40%) as a yellow oil.

The racemic material was separated by chiral-HPLC to afford the desiredisomer (shown on the bottom, above) (1.8 g, 45%).

Synthesis of (S)-4-(2,2-dimethyl-1,3-dioxolan-4-yl)benzenamine

A mixture of (S)-2,2-dimethyl-4-(4-nitrophenyl)-1,3-dioxolane (3.6 g,16.1 mmol) and 5% palladium on carbon (50% wet, 700 mg) in methanol (30mL) was stirred under 1 atm hydrogen atmosphere (H₂ balloon) at RT for16 h. After the reaction mixture was filtered through a pad of Celite,the filtrate was concentrated to afford the title compound (3.1 g, 100%)as a yellow solid. MS (ES+) C₁₁H₁₅NO₂ requires: 193. found: 194 [M+H]⁺.

Synthesis of tert-butyl4-(5-acetylpyrimidin-2-yl)piperazine-1-carboxylate

To a mixture of tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5.0 g, 14.6 mmol),palladium diacetate (240 mg, 1.46 mmol) and triphenylphosphine (376 mg,2.92 mmol) in dioxane (100 mL) was added tributyl(1-ethoxyvinyl)stannane(5.3 mL, 16.1 mL) under N₂, and the reaction mixture was stirred at 80°C. overnight. The reaction was cooled to RT and diluted with THF (100mL), followed by the addition of 2 N HCl (100 mL). The mixture wasstirred at RT for 30 mins, and LCMS showed the reaction was completed.The reaction mixture was diluted with ethyl acetate (200 mL). Theorganic phase was separated, washed with water (3×100 mL), dried oversodium sulfate, filtered and concentrated. The residue was purified bysilica gel column chromatography to afford the title compound (3.0 g,67%). MS (ES+) C₁₅H₂₂N₄O₃ requires: 306. found: 251 [M−56+H]⁺.

Synthesis of 1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanone

To a solution of -butyl4-(5-acetylpyrimidin-2-yl)piperazine-1-carboxylate (4.5 g, 14.7 mmol) indichloromethane (80 mL) was added trifluoroethyl acetate (20 mL), andthe mixture was stirred at RT for 3 h. LCMS showed the reaction wascompleted. The reaction mixture was neutralized with sodium carbonatesolution and extracted with dichloromethane. The organic layer was driedover sodium sulfate, filtered and concentrated to afford the titlecompound as a light yellow solid (2.6 g, 86%), which was directly usedin the next step without further purification. MS (ES+) C₁₀H₁₄N₄Orequires: 206. found: 207 [M+H]⁺.

Synthesis of1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol

To a solution of 1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanone (1.8 g,8.73 mmol) in dry THF (100 mL) was added (4-fluorophenyl)magnesiumbromide (1 M in THF, 87.3 mL) at 0° C. under N₂. The mixture was stirredat RT for 3 h, then quenched with ammonium chloride solution andextracted with dichloromethane (300 mL). The organic layer was driedover sodium sulfate, filtered and concentrated. The residue was purifiedby Combi-flash (dicholomethane:methanol=10:1) to give the title compound(1.02 g, 38%) as a yellow solid.

Chiral separation of1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol

The racemate compound (1.02 g) was separated by chiral HPLC to affordenantiomer 1 (320 mg) and enantiomer 2 (220 mg). MS (ES+) C₁₆H₁₉FN₄Orequires: 302. found: 303 [M+H]⁺. The absolute configuration wasassigned randomly.

Chiral separation conditions: Chiral column: OZ—H (4.6*250 mm, Sum);Mobile phase: co-solvent EtOH (0.1% DEA)

Synthesis of (4-nitrophenyl)methanesulfonamide

To a solution of (4-nitrophenyl)methanesulfonyl chloride (4 g, 17 mmol)in acetonitrile (100 mL) was added a solution of ammonium carbonate (3g, 31.3 mmol) in ammonia (50 mL). The reaction mixture was stirred for 1h, and TLC indicated the starting material consumed completely. Theorganic solvent was removed under reduced pressure. Addition of water(10 mL) led to precipitate formation. The solid was collected, washedwith water (2×5 mL), and dried to give (4-nitrophenyl)methanesulfonamide(3.4 g, 93%) as a white solid. MS (ES+) C₇H₈N₂O₄S requires: 216. found:217 [M+H]⁺.

Synthesis of 6-nitro-3,4-dihydro-1H-benzo[d][1,2]thiazine 2,2-dioxide

To a mixture of (4-nitrophenyl)methanesulfonamide (864 mg, 4.0 mmol) ands-trioxane (120 mg, 4.0 mmol) in 1,2-dichoroethane (10 mL) was addedtrifluoromethanesulfonic acid (1.5 mL), followed by the addition oftrifluoromethanesulfonic anhydride (1.5 mL, 4.0 mmol). The reactionmixture was stirred at 35° C. for 2 hours and refluxed overnight. Themixture was then diluted with dichloromethane (100 mL) and washed withwater (100 mL) and brine (50 mL). The solvents were evaporated and theresidue was purified by Prep-HPLC to give6-nitro-3,4-dihydro-1H-benzo[d][1,2]thiazine 2,2-dioxide (210 mg, 23%)as a gray solid. MS (ES+) C₈H₈N₂O₄S requires: 228. found: 229 [M+H]⁺.

Synthesis of tert-butyl6-nitro-1,4-dihydro-3H-benzo[d][1,2]thiazine-3-carboxylate 2,2-dioxide

To a solution of compound 3 (40 mg, 0.17 mmol) and diisopropylethylamine(44 mg, 0.34 mmol) in dichloromethane (5 mL) was added di-tert-butyldicarbonate (57 mg, 0.26 mmol). The mixture was then stirred at RT for 1h, and then diluted with dichloromethane (100 mL). The organic layer waswashed with water (100 mL) and brine (50 mL), concentrated and dried togive tert-butyl6-nitro-1,4-dihydro-3H-benzo[d][1,2]thiazine-3-carboxylate 2,2-dioxide(crude, 60 mg) as a yellow solid. MS (ES+) C₁₃H₁₆N₂O₆S requires: 328.found: 351 [M+Na]⁺.

Synthesis of tert-butyl6-Amino-1,4-dihydro-3H-benzo[d][1,2]thiazine-3-carboxylate 2,2-dioxide

A suspension of compound 4 (220 mg, 0.738 mmol) and Pd/C (50 mg) inmethanol (30 mL) was stirred at 80° C. under 1 atm hydrogen overnight.The reaction mixture was cooled to RT, and filtered through a pad ofcelite. The filtrate was concentrated to afford the tert-butyl6-Amino-1,4-dihydro-3H-benzo[d][1,2]thiazine-3-carboxylate 2,2-dioxide(160 mg, 79.2%) as a white solid. MS (ES+) C₂₆H₃₄N₄O₁₀S₂ requires: 626.found: 627 [M+H]⁺.

Synthesis of 5-bromo-2-chloropyrimidin-4-ol

To a solution of 5-bromo-2,4-dichloropyrimidine (10 g, 44.2 mmol) in THF(135 mL) was added sodium hydroxide solution (3 M, 45 mL), and themixture was stirred overnight at RT. The solvent was evaporated, and theresidue was diluted with water (100 mL). The aqueous solution was cooledto 0° C., brought to pH 2-3 with 1 N HCl and then extracted withmethanol/dichloromethane (5%, 5×100 mL). The organic layers wereseparated, combined, dried over sodium sulfate, filtered andconcentrated to give 5-bromo-2-chloropyrimidin-4-ol (6.5 g, 71%) as ayellow solid. MS (ES+) C₄H₂BrClN₂O requires: 208, 210. found: 209, 211[M+H]⁺.

Synthesis of tert-butyl4-(5-bromo-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate

A solution of 5-bromo-2-chloropyrimidin-4-ol (6.5 g, 31 mmol),tert-butyl piperazine-1-carboxylate (6.5 g, 35 mmol) in propan-2-ol (200mL) and diisopropylethylamine (10 mL) was stirred at 80° C. overnight.The mixture was cooled to RT and then concentrated. The residue waspurified by silica gel chromatography eluting with ethylacetate:petroleum ether (100:1) to give tert-butyl4-(5-bromo-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (9 g, 80%)as a yellow solid. MS (ES+) C₁₃H₁₉BrN₄O₃ requires: 358, 360. found: 303,305 [M+H−56]⁺.

Synthesis of 5-benzyl-2-(piperazin-1-yl)pyrimidin-4-ol

To a solution of tert-butyl4-(5-bromo-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (20 g, 56mmol) and Pd(Amphos)Cl₂ (4.0 g 5.6 mmol) in THF (200 mL, dry) was addedbenzylzinc(II) bromide (168 mL, 168 mmol) under argon and the mixturewas stirred at 60° C. overnight. The reaction mixture was diluted withethyl acetate (1.5 L), filtered and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=1:1 to 100% ethyl acetate) to give5-benzyl-2-(piperazin-1-yl)pyrimidin-4-ol (8.2 g, 54%) as a pale yellowsolid. MS (ES+) C₁₅H₁₈N₄O requires: 270. found: 271 [M+H]⁺.

Synthesis of tert-butyl4-(5-benzyl-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate

To a solution of 5-benzyl-2-(piperazin-1-yl)pyrimidin-4-ol (8.0 g, 29.5mmol) and triethylamine (8.9 g, 88.5 mmol) in THF (90 mL) was addeddi-tert-butyl dicarbonate (7.7 g, 35.4 mmol). The mixture was stirred atRT overnight, and then diluted with ethyl acetate (300 mL). The organicphase was washed with water (300 mL) and brine (150 mL), dried oversodium sulfate, and evaporated under reduced pressure. The residue waspurified by silica gel chromatography (petroleum ether/ethyl acetate=2:1to 1:2) to give tert-butyl4-(5-benzyl-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (4.5 g,41%) as a pale yellow solid. MS (ES+) C₂₀H₂₆N₄O₃ requires: 370. found:371 [M+H]⁺.

Synthesis of tert-butyl4-(5-benzyl-4-(trifluoromethylsulfonyloxy)pyrimidin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-benzyl-4-hydroxypyrimidin-2-yl)piperazine-1-carboxylate (4.3 g,11.5 mmol), triethylamine (3.2 mL, 23 mmol) andN,N-dimethylpyridin-4-amine (183 mg, 1.15 mmol) in dichloromethane (40mL) was added trifluoromethanesulfonic anhydride (2.3 mL, 13.9 mmol).The reaction mixture was stirred at RT for 1 h, and diluted withdichloromethane (200 mL). The organic phase was washed with water (200mL) and brine (100 mL), dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography(petroleum ether/ethyl acetate=10:1 to 5:1) to give tert-butyl4-(5-benzyl-4-(trifluoromethylsulfonyloxy)pyrimidin-2-yl)piperazine-1-carboxylate(2.4 g, 41%) as a yellow oil. MS (ES+) C₂₁H₂₅F₃N₄O₅S requires: 502.found: 525 [M+Na]⁺.

Synthesis of tert-butyl4-(5-benzyl-4-methylpyrimidin-2-yl)piperazine-1-carboxylate

To a mixture of tert-butyl4-(5-benzyl-4-(trifluoromethylsulfonyloxy)pyrimidin-2-yl)piperazine-1-carboxylate(280 mg, 0.56 mmol) and iron (III) acetylacetonate (21 mg, 0.06 mmol) inTHF (5 mL, dry) and 1-methyl-2-pyrrolidinone (1 mL) was addedmethylmagnesium chloride (1.68 mL, 1.68 mmol). The reaction mixture wasstirred at RT for 1 h, and diluted with ethyl acetate (100 mL) and sat.aq. NH₄Cl (100 mL). The organic layer was washed with brine (100 mL),dried over sodium sulfate, filtered and evaporated to give tert-butyl4-(5-benzyl-4-methylpyrimidin-2-yl)piperazine-1-carboxylate (crude, 250mg) as a yellow solid. MS (ES+) C₂₁H₂₈N₄O₂ requires: 368. found: 369[M+H]⁺.

Synthesis of 5-benzyl-4-methyl-2-(piperazin-1-yl)pyrimidine

To a solution of tert-butyl4-(5-benzyl-4-methylpyrimidin-2-yl)piperazine-1-carboxylate (250 mg,0.68 mmol) in dioxane (2 mL) was added 4 M HCl-dioxane (2 mL). Thereaction mixture was stirred at RT for 2 h and then concentrated toafford crude 5-benzyl-4-methyl-2-(piperazin-1-yl)pyrimidine. MS (ES+)C₁₆H₂₀N₄ requires: 268. found: 269 [M+H]⁺.

Synthesis of tert-butyl4-(5-benzylpyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

A solution of 5-benzyl-2-chloropyrimidine (944 mg, 4.626 mmol),tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (1.0 g, 6.939 mmol)and diisopropylethylamine (1.8 g, 13.878 mmol) in dioxane (100 mL) wasstirred at 110° C. for two days. The reaction mixture was cooled to roomtemperature, concentrated and directly purified by silica gelchromatography eluting with petroleum ether:ethyl acetate=1:1, to affordtert-butyl4-(5-benzylpyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate(400 mg, 15%) as a white solid. MS (ES+) C₂₁H₂₈N₄O₃ requires: 384.found: 385 [M+H]⁺.

Synthesis of (1-(5-benzylpyrimidin-2-yl)piperazin-2-yl)methanol

A solution of tert-butyl4-(5-benzylpyrimidin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate(400 mg, 1.042 mmol) in 4 M HCl/dioxane (20 mL) was stirred at roomtemperature for 2 h. The reaction mixture was concentrated under reducedpressure to afford (1-(5-benzylpyrimidin-2-yl)piperazin-2-yl)methanolHCl salt (294 mg, 100%). MS (ES+) C₁₆H₂₀N₄O requires: 284. found: 285[M+H]⁺.

Synthesis of benzyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (957 mg, 2.6 mmol)in dioxane (20 mL) was added 4 M HCl-dioxane (20 mL). The reactionmixture was stirred at room temperature overnight and concentrated toafford crude phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone which wasused in the next step directly.

To a solution of phenyl(2-(piperazin-1-yl)pyrimidin-5-yl)methanone(crude, 2.6 mmol assumed) and triethylamine (780 mg, 7.8 mmol) indichloromethane (10 mL) was added benzyl chloroformate (663 mg, 3.9mmol). The reaction mixture was stirred at room temperature for 2 hours,and diluted with dichloromethane (100 mL). The organic phase was washedwith water (100 mL) and brine (50 mL), dried over sodium sulfate,filtered and concentrated. The residue was purified by silica gelchromatography (etroleum ether/ethyl acetate=4:1-2:1) to give benzyl4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (600 mg, 57%) as ayellow solid. MS (ES+) C₂₃H₂₂N₄O₃ requires: 402. found: 403 [M+H]⁺.

Synthesis of benzyl4-(5-(difluoro(phenyl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate

Benzyl 4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (360 mg, 0.37mmol) in diethylaminosulfur trifluoride (2 mL) was stirred at 90° C.overnight. The reaction mixture was diluted with ethyl acetate (100 mL),washed with sat. aq. sodium bicarbonate (100 mL) and brine (100 mL), andevaporated in vacuum. The residue was purified by silica gelchromatography (petroleum ether/ethyl acetate=10:1) to give benzyl4-(5-(difluoro(phenyl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate(180 mg, 47%) as a brown solid. MS (ES+) C₂₃H₂₂F₂N₄O₂ requires: 424.found: 425 [M+H]⁺.

Synthesis of 5-(difluoro(phenyl)methyl)-2-(piperazin-1-yl)pyrimidine

To a solution of4-(5-(difluoro(phenyl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate(180 mg, 0.42 mmol) in chloroform (5.0 mL) was added iodotrimethylsilane(0.8 mL) and the mixture was stirred at room temperature for 0.5 h. Thereaction was quenched by methanol (1.0 mL), followed by the addition of2 N HCl/dioxane (2.0 mL) and evaporated to dryness. The residue wasdissolved in methanol (1.5 mL) and dropwise added into acetone (100 mL).The solid was collected by filtration and washed with acetone (10 mL) toafford crude 5-(difluoro(phenyl)methyl)-2-(piperazin-1-yl)pyrimidine (88mg) as a yellow solid. MS (ES+) C₁₅H₁₆F₂N₄ requires: 290. found: 291[M+H]⁺.

Synthesis of (S)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol

To a solution of 5-methyl-4-nitro-1H-pyrazole (2.5 g, 19.7 mmol) inacetonitrile (100 mL) was added (S)-2-methyloxirane (1.37 g, 23.6 mmol)and cesium carbonate (19.3 g, 59.1 mmol). The mixture was stirred at 30°C. for 7 days, then cooled to room temperature and filtered. Thefiltrate was concentrated under reduced pressure, and the residue waspurified by Prep-HPLC and then chiral-HPLC to give(S)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol (0.33 g) as ayellowish solid. MS (ES+) C₇H₁₁N₃O₃ requires: 185. found: 186 [M+H]⁺.

Synthesis of (S)-1-(4-amino-5-methyl-1H-pyrazol-1-yl)propan-2-ol

To a solution of (S)-1-(5-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-ol(100 mg, 0.54 mmol) in methanol (20 mL) was added 10% Pd/C (20 mg). Thereaction mixture was stirred under 1 atm H₂ atmosphere at roomtemperature overnight, and filtered through a pad of Celite. Thefiltrate was concentrated to give(S)-1-(4-amino-5-methyl-1H-pyrazol-1-yl)propan-2-ol (96 mg, crude) as ayellowish oil. MS (ES+) C₇H₁₃N₃O requires: 155. found: 156 [M+H]⁺.

Synthesis of tert-butyl4-(5-(1-phenylvinyl)pyrimidin-2-yl)piperazine-1-carboxylate

To a solution of Ph₃PCH₃Br (1.69 g, 5.45 mmol) in dry THF (20 mL) wasadded n-butyl lithium (2.06 mL, 2.5 M in hexane) at room temperature.The mixture was stirred for 1.5 h, and the yellow solution was directlyused in the next reaction.

The above solution was added to a solution of tert-butyl4-(5-benzoylpyrimidin-2-yl)piperazine-1-carboxylate (1 g, 2.7 mmol) indry THF (20 mL) at 0° C., and the reaction solution was stirred at roomtemperature for 2 h. The reaction was quenched by water (20 mL) andextracted with ethyl acetate (200 mL). The organic layer was separated,dried over sodium sulfate, filtered and concentrated. The residue waspurified by silica gel chromatography eluting with petroleum ether:ethylacetate 10:1 to give tert-butyl4-(5-(1-phenylvinyl)pyrimidin-2-yl)piperazine-1-carboxylate (890 mg,89%) as a white solid. MS (ES+) C₂₁H₂₆N₄O₂ requires: 366. found: 367[M+H]⁺.

Synthesis of tert-butyl4-(5-(1-phenylcyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-(1-phenylvinyl)pyrimidin-2-yl)piperazine-1-carboxylate (366 mg, 1.0mmol) in THF (20 mL) was added trimethylsulfoxonium iodide (1.1 g 5.0mmol) in dimethyl sulfoxide (7 mL). The reaction mixture was stirred at80° C. for 4 days, and diluted with ethyl acetate (200 mL). The organicphase was washed with water (200 mL) and brine (100 mL), dried oversodium sulfate, and concentrated. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=20:1) to give tert-butyl4-(5-(1-phenylcyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate (40mg, 10%) as a yellow solid. MS (ES+) C₂₂H₂₈N₄O₂ requires: 380. found:381 [M+H]⁺.

Synthesis of 5-(1-phenylcyclopropyl)-2-(piperazin-1-yl)pyrimidine

To a solution of tert-butyl4-(5-(1-phenylcyclopropyl)pyrimidin-2-yl)piperazine-1-carboxylate (30mg, 0.08 mmol) in dioxane (2 mL) was added 4 M HCl-dioxane (2 mL). Thereaction mixture was stirred at room temperature overnight and thenconcentrated to afford crude5-(1-phenylcyclopropyl)-2-(piperazin-1-yl)pyrimidin. MS (ES+) C₁₇H₂₀N₄requires: 280. found: 281 [M+H]⁺.

Synthesis of (S,Z)-tert-butyl4-(5-((tert-butylsulfinylimino)(4-fluorophenyl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (4.0 g,10.4 mmol), (S)-2-methylpropane-2-sulfinamide (2.5 g, 20.7 mmol) in THF(60 mL) was added titanium ethoxide (20 mL) at room temperature. Theresultant solution was heated at 70° C. overnight. After that, thereaction was cooled to room temperature, diluted with ethyl acetate (200mL) and saturated aqueous sodium bicarbonate (500 mL). The mixture wasfiltered through Celite. The filtrate was separated. Aqueous layer wasextracted with ethyl acetate (200 mL×3). Then organic layers werecombined, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by silica gel column (petroleum ether:ethylacetate 2:1) to afford the title compound (3.3 g, yield 66%) as a yellowsolid. MS (ES+) requires: 489. found 490 [M+H]⁺; purity: 95% (UV at 254nm).

Synthesis of tert-butyl4-(5-(1-((S)-1,1-dimethylethylsulfinamido)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate

To a solution of (S,Z)-tert-butyl4-(5-((tert-butylsulfinylimino)(4-fluorophenyl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate(3.0 g, 6.1 mmol) in THF (20 mL) was dropwise added methyl magnesiumbromide (2.1 mL, 6.1 mmol, 3 M in ethyl ether) slowly at −60° C. undernitrogen. After addition, the mixture was allowed to warm to roomtemperature and stirred for 2 h. Then, the reaction was quenched bymethanol (20 mL) and saturated aqueous ammonium chloride (50 mL), andextracted with ethyl acetate (50 mL×3). The combined organic layers weredried over sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by silica gel column(dichloromethane:methanol=40:1) to give the title compound 3 (2.5 g,yield 77%) as a yellow solid. MS (ES+) requires: 505. found 506 [M+Na]⁺;purity: 100% (UV at 254 nm).

Preparation of(S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine

To a solution of tert-butyl4-(5-(1-((S)-1,1-dimethylethylsulfinamido)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate(2.5 g, 5.0 mmol) in dioxane (5.0 mL) was dropwise added HCl (4M indioxane, 10 mL). The reaction solution was stirred at room temperatureovernight. Then the solution was concentrated under vacuo to give thetitle compound (1.5 g, crude yield 100%) as a yellow solid. MS (ES+)C₁₆H₂₀FN₅ requires: 301, found 302 [M+H]⁺; purity: 100% (UV at 254 nm).The above racemate (1.5 g) was separated by Chiral-HPLC to afford thedesired single enantiomer (600 mg, 40%) as a yellow solid. MS (ES+)C₁₆H₂₀FN₅ requires: 301. found: 302 [M+H]⁺.

The synthetic protocol that can be used to prepare the compoundsdisclosed herein is shown below. The NMR and LC MS data obtained forcompounds disclosed herein are also shown below.

Compound Synthetic LC/MS Number Protocol ¹H NMR M + 1 4 3 This spectrumcontains some rotamers in the aromatic region - 1H 416 NMR (400 MHz,DMSO-d6) δ 12.54 (s, 1H), 9.52 (d, J = 61.6 Hz, 2H), 8.30 (s, 2H), 8.14(s, 1H), 7.82 (s, 1H), 7.55 (d, J = 21.1 Hz, 1H), 7.34-7.11 (m, 5H),3.80 (q, J = 9.2, 7.5 Hz, 10H). 5 3 416 6 2 ¹H-NMR (500 MHz, DMSO-d₆) δppm 9.66, 9.53 (s, s, 1H), 8.40 (d, 2H, J = 4.5 Hz), 8.31, 8.17 (s, s,1H), 7.84 (s, 1H), 7.51, 7.50 (s, s, 1H), 6.68 (t, 1H, J = 5.0 Hz),4.11-4.07 (m, 2H), 3.86-3.66 (m, 10H), 3.39-3.34 (m, 1H), 2.67-2.64 (m,3H), 2.38-2.34 (br, 1H). 7 3 1H NMR (400 MHz, DMSO-d6) δ 9.75-9.62 (m,1H), 8.31 (s, 426 2H), 8.26 (s, 1H), 7.75-7.66 (m, 2H), 7.37-7.13 (m,7H), 7.04-6.93 (m, 1H), 3.93-3.68 (m, 10H). 9 5 426 10 3 This spectrumcontains some rotamers in the aromatic region: 1H 429 NMR (400 MHz,DMSO-d6) δ 9.62, 9.48 (s, 1H), 8.31, 8.26 (s, 2H), 8.14 (s, 1H), 7.82,7.78 (s, 1H), 7.47, 7.42 (s, 1H), 7.34-7.11 (m, 5H), 3.87-3.71 (m, 10H).11 3 ¹H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.31 (m, 3H), 4307.34-7.15 (m, 5H), 6.71 (s, 1H), 3.81 (m, 10H), 3.41-3.22 (m, 2H), 2.40(m, 3H). 12 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.31 (d, J = 1.0Hz, 440 2H), 8.22 (s, 1H), 7.34-7.14 (m, 5H), 7.06 (s, 1H), 6.91 (t, J =7.9 Hz, 1H), 6.82-6.76 (m, 1H), 6.27-6.19 (m, 1H), 5.12 (s, 2H),3.89-3.72 (m, 10H). 13 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.31(s, 2H), 441 8.25 (s, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 2.4Hz, 1H), 7.44 (t, J = 2.4 Hz, 1H), 7.33-7.14 (m, 5H), 5.37 (s, 2H), 3.80(m, 10H). 14 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.31 (s, 2H),454 8.25 (s, 1H), 7.78 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.35-7.14 (m,6H), 6.96 (d, J = 7.6 Hz, 1H), 3.87-3.74 (m, 10H), 3.70 (s, 2H). 15 3 ¹HNMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.31 (s, 2H), 455 8.25 (s, 1H),7.83 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.34-7.13 (m, 6H), 6.92 (d, J =7.5 Hz, 1H), 5.17 (t, J = 5.7 Hz, 1H), 4.47 (d, J = 5.7 Hz, 2H),3.91-3.70 (m, 10H). 16 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.31(s, 2H), 455 8.25 (s, 1H), 7.64 (dd, J = 8.6, 2.4 Hz, 2H), 7.35-7.14 (m,7H), 4.43 (s, 2H), 3.90-3.72 (m, 10H). 17 3 ¹H-NMR (400 MHz, DMSO-d₆) δppm 10.05 (s, 1H), 8.36 (s, 1H), 8.32 (s, 2H), 7.98 (d, 1H, J = 5.6 Hz),7.31-7.18 (m, 7H), 3.86-3.76 (m, 13H). 19 1 ¹H-NMR (400 MHz, DMSO-d₆) δppm 9.67, 9.53 (s, s, 1H), 8.29-8.16 (m, 3H), 7.83 (s, 1H), 7.51-7.48(m, 1H), 4.21-4.05 (m, 2H), 3.83-3.68 (m, 11H), 3.51-3.42 (m, 1H),2.82-2.63 (m, 3H), 2.45-2.39 (m, 1H), 1.80-1.76 (m, 1H), 0.89-0.86 (m,2H), 0.66-0.63 (m, 2H). 22 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H),8.53 (br.s, 1H), 467 8.31 (s, 2H), 8.29 (s, 1H), 7.82 (d, J = 8.0 Hz,1H), 7.61 (dd, J = 7.8, 1.7 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.29 (t,J = 7.4 Hz, 2H), 7.25-7.14 (m, 3H), 3.94-3.72 (m, 14H), 2.57 (s, 3H). 233 ¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (s, 1H), 8.39 (s, 1H), 468 8.32 (d, J= 1.4 Hz, 2H), 7.91 (s, 1H), 7.70 (dd, J = 8.0, 2.2 Hz, 1H), 7.56-7.48(m, 1H), 7.44-7.12 (m, 6H), 3.94-3.69 (m, 10H). 24 3 ¹H NMR (400 MHz,DMSO-d6) δ 9.91 (s, 1H), 8.31 (s, 3H), 468 7.88-7.72 (m, 5H), 7.35-7.12(m, 6H), 3.91-3.73 (m, 10H). 25 3 468 26 3 ¹H NMR (400 MHz, DMSO-d6) δ9.64 (s, 1H), 8.31 (s, 2H), 469 8.25 (s, 1H), 7.90 (s, 1H), 7.41 (s,1H), 7.32-7.25 (m, 2H), 7.25-7.15 (m, 4H), 6.95 (d, J = 7.5 Hz, 1H),5.14 (d, J = 4.0 Hz, 1H), 4.73-4.64 (m, 1H), 3.82 (d, J = 21.7 Hz, 10H),1.31 (d, J = 6.4 Hz, 3H). 27 3 ¹H-NMR (500 MHz, DMSO-d₆) δ 9.72, 9.59(br. s., br. s., 1H), 8.32-8.30 (m, 2H), 8.17 (s, 1H), 7.99-7.96 (m,1H), 7.61-7.55 (m, 1H), 7.31-7.18 (m, 5H), 5.22-5.13 (m, 1H), 4.34-3.69(m, 15H). 28 3 ¹H-NMR (500 MHz, DMSO-d₆) δ 9.72, 9.58 (s, s, 1H),8.32-8.29 (m, 2H), 8.17 (s, 1H), 8.00, 7.94 (s, s, 1H), 7.67, 7.61 (s,s, 1H), 7.35-7.15 (m, 5H), 5.66-5.44 (m, 1H), 4.96-4.79 (m, 4H),3.84-3.78 (m, 10H). 29 4 ¹H-NMR (400 MHz, DMSO-d6) δ ppm 9.70 (s, 1H),8.39 (s, 2H), 472 8.27 (s, 1H), 7.72-7.70 (m, 2H), 7.48-7.44 (m, 2H),7.32-7.29 (m, 2H), 7.13-7.08 (m, 2H), 7.00 (t, 1H, J = 7.6 Hz),3.85-3.72 (m, 8H), 2.55 (br, 2H), 1.72 (s, 3H). 30 3 This spectrumcontains some rotamers in the aromatic region: 1H 472 NMR (400 MHz,DMSO-d6) δ 9.61, 9.48 (s, 1H), 8.30, 8.23 (s, 2H), 8.14 (s, 1H), 7.87,7.85 (s, 1H), 7.47, 7.45 (s, 1H), 7.32-7.13 (m, 5H), 4.13 (t, J = 6.1Hz, 2H), 3.79 (m, 10H), 2.82 (t, J = 6.0 Hz, 2H), 2.27 (s, 3H). 31 3¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.63, 9.48 (s, s, 1H), 8.32 (s, 2H),8.16 (s, 1H), 7.86 (s, 1H), 7.49 (s, 1H), 7.29-7.19 (m, 5H), 4.25-4.19(m, 2H), 3.94-3.79 (m, 10H), 3.66 (s, 2H), 3.25 (s, 3H). 32 3 ¹H-NMR(500 MHz, DMSO-d₆) δ ppm 8.33-8.27 (m, 3H), 8.15, 8.05 (s, s, 1H), 7.90,7.88 (s, s, 1H), 7.49 (s, 1H), 7.32-7.20 (m, 5H), 4.03-3.90 (m, 3H),3.80 (m, 11H), 1.04 (d, 3H, J = 6.0 Hz). 33 3 ¹H-NMR (500 MHz, DMSO-d₆)δ ppm 8.34-8.26 (m, 3H), 8.15 (s, 1H), 7.90, 7.87 (s, s, 1H), 7.49 (s,1H), 7.31-7.20 (m, 5H), 4.01-3.94 (m, 3H), 3.82-3.74 (m, 11H), 1.03 (d,3H, J = 6.0 Hz). 36 4 ¹H-NMR (400 MHz, DMSO-d6) δ ppm 9.64, 9.50 (s,1H), 8.38 (s, 477 2H), 8.27, 8.14 (s, 1H), 7.82, 7.79 (s, 1H), 7.47-7.43(m, 3H), 7.11-7.07 (m, 2H), 3.82-3.77 (m, 11H), 2.49 (s, 2H), 1.71 (s,3H). 37 2 476 38 4 ¹H-NMR (400 MHz, CDCl3) δ ppm 8.35 (s, 2H), 8.21 (br.s., 1H), 477 7.80, 7.22 (br. s., br. s., 1H), 7.61-7.55 (m, 1H),7.43-7.38 (m, 2H), 7.04-7.00 (m, 2H), 3.90 (br. s., 11H), 2.30 (br. s.,1H), 1.92 (s, 3H). 39 4 ¹H-NMR (400 MHz, CDCl3) δ ppm 8.35 (s., 2H),8.20 (br. s., 1H), 477 7.77, 7.32 (br. s., br. s., 1H), 7.61-7.56 (m,1H), 7.42-7.38 (m, 2H), 7.05-7.00 (m, 2H), 3.89 (br. s., 11H), 2.32 (br.s., 1H), 1.92 (s., 3H). 41 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H),8.31, 8.30 (s, 2H), 480 8.24 (s, 1H), 7.42 (s, 1H), 7.37 (dd, J = 8.2,2.3 Hz, 1H), 7.34-7.25 (m, 2H), 7.25-7.15 (m, 3H), 6.99 (d, J = 8.4 Hz,1H), 3.89-3.71 (m, 12H), 2.96 (t, J = 5.9 Hz, 2H), 2.64 (t, J = 5.9 Hz,2H). 42 3 480 43 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.61, 8.56(s, 1H), 481 8.32, 8.30 (s, 2H), 8.27 (s, 1H), 7.86-7.73 (m, 1H),7.35-7.14 (m, 5H), 3.97-3.65 (m, 12H), 3.00 (t, J = 6.0 Hz, 1H),2.94-2.79 (m, 2H), 2.70 (t, J = 5.8 Hz, 1H). 44 1 ¹H NMR (400 MHz,DMSO-d6) δ 9.56 (s, 1H), 8.52-8.42 (m, 481 1H), 8.35 (s, 2H), 8.24 (s,1H), 7.76-7.67 (m, 2H), 7.48-7.34 (m, 2H), 7.31 (d, J = 7.7 Hz, 1H),7.21 (dd, J = 7.5, 4.7 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 3.94 (s, 2H),3.88 (s, 2H), 3.80 (br.s., 8H), 3.00 (t, J = 6.0 Hz, 2H), 2.67 (t, J =5.9 Hz, 2H). 45 1 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.55 (br, 1H), 8.52(s, 1H), 8.42 (d, 1H, J = 4.5 Hz), 8.35 (s, 2H), 8.24 (s, 1H), 7.64 (d,1H, J = 8.0 Hz), 7.41 (s, 1H), 7.37 (d, 1H, J = 8.0 Hz), 7.31 (dd, 1H, J= 8.0, 4.7 Hz), 6.99 (d, 1H, J = 8.0 Hz), 3.83 (br. s., 12H), 2.95 (d,2H, J = 6.0 Hz), 2.63 (t, 2H, J = 6.0 Hz). 46 5 ¹H NMR (400 MHz,Methanol-d4) δ 8.22 (s, 3H), 7.61-7.48 (m, 482 2H), 7.39-7.29 (m, 2H),7.22 (d, J = 8.4 Hz, 1H), 7.09 (tt, J = 7.3, 1.1 Hz, 1H), 7.00-6.92 (m,2H), 4.36 (s, 2H), 3.98-3.84 (m, 8H), 3.51 (t, J = 6.4 Hz, 2H), 3.09 (t,J = 6.4 Hz, 2H). 47 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.65 (s,1H), 482 8.31 (s, 2H), 8.24 (s, 1H), 7.38-7.01 (m, 9H), 3.82 (m, 10H),2.03 (s, 3H). 48 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.31 (s,2H), 482 8.25 (d, J = 2.0 Hz, 2H), 7.85 (s, 1H), 7.43 (s, 1H), 7.34-7.14(m, 6H), 6.98 (d, J = 7.6 Hz, 1H), 3.87-3.75 (m, 10H), 3.65 (q, J = 6.5Hz, 1H), 2.18 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H). 49 3 ¹H NMR (400 MHz,DMSO-d6) δ 9.65 (s, 1H), 8.31 (s, 2H), 482 8.25 (s, 1H), 7.86 (s, 1H),7.45 (d, J = 8.4 Hz, 1H), 7.33-7.14 (m, 6H), 6.89 (d, J = 7.5 Hz, 1H),3.93-3.70 (m, 10H), 3.34 (s, 2H), 2.15 (s, 6H). 50 3 ¹H NMR (400 MHz,DMSO-d6) δ 9.62 (s, 1H), 8.31 (s, 2H), 483 8.24 (s, 1H), 7.36 (s, 1H),7.28 (t, J = 7.4 Hz, 2H), 7.21 (m, 4H), 7.09 (d, J = 7.6 Hz, 1H), 4.97(s, 1H), 3.82 (m, 10H), 3.65-3.53 (m, 3H), 3.19-3.07 (m, 3H), 1.42 (s,6H). 51 3 This spectrum contains some rotamers in the aromatic region:1H 484 NMR (400 MHz, DMSO-d6) δ 9.61, 9.47 (s, 1H), 8.30, 8.25 (s, 2H),8.13 (s, 1H), 7.81 (s, 1H), 7.45 (d, J = 11.5 Hz, 1H), 7.32-7.13 (m,5H), 4.25 (dd, J = 23.2, 7.4 Hz, 2H), 3.88-3.70 (m, 10H), 3.53-3.42 (m,2H), 3.05-2.85 (m, 2H) - one peak is obscured partially by the watersignal. 52 3 This spectrum contains some rotamers in the aromaticregion: 1H 484 NMR (400 MHz, DMSO-d6) δ 9.68-9.45 (m, 1H), 8.35-8.23 (m,2H), 8.14 (d, J = 4.5 Hz, 1H), 7.89 (s, 1H), 7.48 (d, J = 18.8 Hz, 1H),7.31-7.14 (m, 5H), 4.91-4.77 (mz, 1H), 3.90-3.67 (m, 10H), 3.20-3.10 (m,1H), 3.07-2.80 (m, 3H), 2.76-2.58 (m, 0H), 2.40-2.22 (m, 1H), 2.17 (dd,J = 13.8, 7.2 Hz, 1H), 1.98 (s, 1H). 53 3 This spectrum contains somerotamers in the aromatic region: 1H 484 NMR (400 MHz, DMSO-d6) δ9.71-9.44 (m, 1H), 8.35-8.22 (m, 2H), 8.13 (d, J = 2.8 Hz, 1H),7.94-7.82 (m, 1H), 7.57-7.39 (m, 1H), 7.33-7.11 (m, 5H), 4.92-4.75 (m,1H), 3.89-3.70 (m, 10H), 3.08-2.94 (m, 1H), 2.94-2.76 (m, 2H), 2.76-2.60(m, 1H), 2.40-2.24 (m, 1H), 2.23-2.07 (m, 1H), 2.07-1.89 (m, 1H). 54 3485 55 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.32 (s, 2H), 4857.56 (d, J = 8.5 Hz, 2H), 7.37-7.08 (m, 5H), 6.89 (d, J = 8.5 Hz, 2H),4.92 (d, J = 4.9 Hz, 1H), 4.65 (t, J = 5.6 Hz, 1H), 3.96 (dd, J = 9.5,4.0 Hz, 1H), 3.80 (m, 10H), 3.44 (t, J = 5.5 Hz, 2H). 56 3 ¹H-NMR (400MHz, DMSO-d6) δ ppm 9.64 (s, 1H), 8.31 (s, 2H), 485 8.25 (s, 1H), 7.63(d, 2H, J = 8.4 Hz), 7.31-7.17 (m, 7H), 5.15 (d, 1H, J = 4.0 Hz), 4.69(t, 1H, J = 5.6 Hz), 4.49 (dd, 1H, J = 10 Hz, J = 5.6 Hz), 3.83-3.80 (m,10H), 3.39 (t, 1H, J = 5.6 Hz). 57 3 ¹H-NMR (400 MHz, DMSO-d6) δ ppm9.65 (s, 1H), 8.32 (s, 2H), 485 8.26 (s, 1H), 7.63 (d, 2H, J = 8.4 Hz),7.31-7.17 (m, 7H), 5.15 (d, 1H, J = 4.0 Hz), 4.69 (t, 1H, J = 5.6 Hz),4.49 (dd, 1H, J = 10 Hz, J = 5.6 Hz), 3.83-3.80 (m, 10H), 3.41 (t, 1H, J= 5.6 Hz). 58 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.31 (s, 2H),485 8.17 (s, 1H), 7.62 (s, 1H), 7.29 (mz, 2H), 7.26-7.14 (m, 3H), 6.49(d, J = 8.9 Hz, 1H), 6.30 (t, J = 5.8 Hz, 1H), 4.70 (t, J = 5.3 Hz, 1H),3.78 (m, 10H), 3.55-3.46 (m, 2H) - one peak obscured by water signal. 603 ¹H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.31 (s, 2H), 486 8.13 (d, J= 7.8 Hz, 1H), 7.87 (d, J = 13.9 Hz, 1H), 7.45 (s, 1H), 7.30-7.15 (m,5H), 4.22-4.13 (m, 2H), 3.81 (d, J = 15.3 Hz, 10H), 2.59 (t, J = 6.3 Hz,2H), 2.20-2.11 (m, 6H). 61 3 This spectrum contains some rotomers in thearomatic region: ¹H 486 NMR (400 MHz, DMSO-d6) δ 9.61, 9.48 (s, 1H),8.30, 8.27 (s, 2H), 8.14 (s, 1H), 7.87, 7.84 (s, 1H), 7.47, 7.45 (s,1H), 7.31-7.25 (m, 2H), 7.24-7.15 (m, 3H), 4.20-4.02 (m, 3H), 3.79 (t, J= 11.9 Hz, 12H), 2.82 (t, J = 6.0 Hz, 2H), 2.27 (s, 3H). 62 3 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 9.64, 9.52 (s, s, 1H), 8.32 (s, 2H), 8.16 (s,1H), 7.94, 7.90 (s, s, 1H), 7.45 (s, 1H), 7.34-7.26 (m, 2H), 7.25-7.14(m, 3H), 4.71, 4.69 (s, s, 1H), 3.99, 3.97 (s, s, 2H), 3.82-3.77 (m,10H), 1.05 (s, 6H). 63 6 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.67, 9.54 (s,s, 1H), 8.42 (s, 2H), 8.29, 8.16 (s, s, 1H), 7.82 (s, 1H), 7.50, 7.48(s, s, 1H), 4.13-4.04 (m, 2H), 3.85-3.69 (m, 11H), 3.44-3.39 (m, 1H),2.77-2.63 (m, 3H), 2.42-2.37 (m, 1H), 1.56-1.52 (m, 1H), 0.89-0.85 (m,2H), 0.73-0.69 (m, 2H). 64 3 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.62, 9.49(s, s, 1H), 8.32 (s, 2H), 8.28, 8.15 (s, s, 1H), 7.90, 7.86 (s, s, 1H),7.49 (s, 1H), 7.29 (t, 2H, J = 7.0 Hz), 7.23 (d, 2H, J = 7.0 Hz), 7.19(t, 1H, J = 7.0 Hz), 5.01-4.84 (m, 1H), 4.74-4.71 (m, 1H), 4.21-4.17 (m,1H), 4.00-3.95 (m, 1H), 3.83-3.76 (m, 11H). 65 3 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 9.63, 9.49 (s, s, 1H), 8.32 (s, 2H), 8.28, 8.15 (s, 1H),7.90, 7.86 (s, s, 1H), 7.46 (s, 1H), 7.31-7.17 (m, 5H), 5.01-4.98 (m,1H), 4.72 (dd, 1H, J = 11.6, 5.6 Hz), 4.18 (dd, 1H, J = 14.0, 3.6 Hz),3.97 (dd, 1H, J = 14.4, 7.6 Hz), 3.84-3.72 (m, 11H), 3.33-3.30 (m, 2H).66 3 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.65, 9.52 (s, s, 1H), 8.32 (s,2H), 8.29, 8.16 (s, s, 1H), 7.91, 7.86 (s, s, 1H), 7.48 (s, 1H),7.31-7.18 (m, 5H), 5.03-4.96 (m, 1H), 4.76-4.72 (m, 1H), 4.19 (dd, 1H, J= 13.5, 3.5 Hz), 3.98 (dd, 1H, J = 14.0, 7.0 Hz), 3.83-3.72 (m, 11H),3.33-3.30 (m, 2H). 67 6 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.65, 9.52 (s,s, 1H), 8.29 (s, 2H), 8.16 (s, 1H), 7.83 (s, 1H), 7.50, 7.47-7.47 (s, s,1H), 4.12-4.03 (m, 2H), 3.84-3.63 (m, 10H), 3.42-3.39 (m, 3H), 2.72-2.57(m, 3H), 2.33 (t, 1H, J = 10.8 Hz), 1.44-1.39 (m, 2H), 0.67-0.61 (m,1H), 0.40-0.38 (m, 2H), 0.03-0.00 (m, 2H). 68 3 ¹H NMR (400 MHz,DMSO-d6) δ 10.20 (s, 1H), 9.63 (s, 1H), 494 8.32 (d, J = 1.0 Hz, 2H),8.23 (s, 1H), 7.40 (s, 1H), 7.34-7.15 (m, 5H), 7.07 (s, 2H), 3.81 (m,10H), 2.80 (t, J = 7.5 Hz, 2H), 2.42 (t, J = 7.6 Hz, 2H). 69 3 ¹H NMR(400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.30 (s, 2H), 494 8.23 (s, 1H),7.45-7.35 (m, 2H), 7.31-7.25 (m, 2H), 7.24-7.16 (m, 3H), 7.01 (d, J =8.2 Hz, 1H), 3.79 (d, J = 6.8 Hz, 10H), 3.44 (s, 2H), 2.74 (t, J = 6.0Hz, 2H), 2.57 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H). 70 3 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 9.53 (br. s., 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.40-7.37(m, 2H), 7.31-7.28 (m, 2H), 7.21-7.15 (m, 3H), 6.99 (d, 1H, J = 8.5 Hz),3.84-3.82 (m, 12H), 2.93 (t, 2H, J = 5.5 Hz), 2.64-2.62 (m, 2H), 2.22(s, 3H). 72 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.37-8.23 (m,494 3H), 7.57-7.44 (m, 2H), 7.32-7.13 (m, 6H), 4.00 (s, 2H), 3.80 (d, J= 11.6 Hz, 10H), 3.17 (t, J = 5.3 Hz, 2H), 2.91-2.83 (m, 2H), 1.75 (q, J= 6.4, 5.3 Hz, 2H). 73 1 ¹H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.22(s, 1H), 495 7.64 (s, 1H), 7.46 (s, 1H), 7.40-7.33 (m, 1H), 7.28-7.20(m, 4H), 7.19-7.13 (m, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.30 (s, 2H), 3.89(s, 2H), 3.81-3.63 (m, 12H), 3.00 (t, J = 5.9 Hz, 2H), 2.67 (t, J = 5.9Hz, 2H). 74 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.31 (m, 3H),496 8.25 (s, 1H), 7.68 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.34-7.12 (m,6H), 6.89 (d, J = 7.6 Hz, 1H), 4.22 (d, J = 5.9 Hz, 2H), 3.80 (d, J =12.2 Hz, 10H), 1.87 (s, 3H). 75 2 496 76 3 ¹H NMR (400 MHz, DMSO-d6) δ9.64 (s, 1H), 8.31 (s, 2H), 496 8.24 (s, 1H), 7.62 (d, J = 2.7 Hz, 1H),7.48 (dd, J = 8.6, 2.6 Hz, 1H), 7.33-7.25 (m, 2H), 7.25-7.13 (m, 3H),6.97 (d, J = 8.6 Hz, 1H), 4.06-3.93 (m, 4H), 3.80 (d, J = 8.9 Hz, 10H),3.22 (t, J = 4.4 Hz, 3H). 77 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H),8.30 (s, 2H), 496 8.20 (s, 1H), 7.61-7.49 (m, 2H), 7.34-7.14 (m, 5H),6.74 (d, J = 8.7 Hz, 2H), 4.97-4.83 (m, 1H), 3.87-3.69 (m, 12H),3.54-3.43 (m, 2H). 78 1 ¹H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H),8.60-8.46 (m, 496 1H), 8.26 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.64 (s,1H), 7.33-7.11 (m, 5H), 6.31 (s, 2H), 3.90-3.57 (m, 12H), 3.00 (t, J =6.0 Hz, 2H), 2.70 (t, J = 6.0 Hz, 2H). 79 3 ¹H-NMR (400 MHz, DMSO-d6) δppm 9.74 (s, 1H), 8.32 (s, 2H), 497 8.27 (s, 1H), 7.72 (d, 2H, J = 8.4Hz), 7.52 (d, 2H, J = 8.4 Hz), 7.32-7.17 (m, 5H), 6.26 (s, 1H), 4.75 (d,2H, J = 6.0 Hz), 4.69 (d, 2H, J = 6.4 Hz), 3.89-3.74 (m, 10H). 80 1¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.54 (br, 1H), 8.34 (s, 2H), 8.24 (s,1H), 7.44-7.29 (m, 3H), 7.11-7.08 (m, 2H), 7.04-6.97 (m, 2H), 3.82 (br,13H), 2.94-2.91 (br, 2H), 2.53-2.48 (m, 2H). 81 2 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 9.32, 9.17 (br. s., br. s., 1H), 8.32 (s, 2H), 8.16 (s,1H), 7.35-7.18 (m, 7H), 6.55 (br, 2H), 5.30-5.26 (br, 1H), 4.68 (br. s.,1H), 3.80-3.77 (m, 11H), 2.93-2.86 (m, 2H), 1.11 (d, 3H, J = 5.5 Hz). 822 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.31, 9.15 (br., s., br. s., 1H), 8.31(s, 2H), 8.15 (s, 1H), 7.34-7.17 (m, 7H), 6.55 (br. s., 2H), 5.26-5.24(m, 1H), 4.66 (d, 1H, J = 5.0 Hz), 3.79-3.77 (m, 11H), 2.95-2.88 (m,2H), 1.10 (d, 3H, J = 6.0 Hz). 83 3 This spectrum contains some rotamersin the aromatic region: ¹H 498 NMR (400 MHz, DMSO-d6) δ 9.61, 9.49 (s,1H), 8.30, 8.27 (s, 2H), 8.14 (s, 1H), 7.82 (s, 1H), 7.49 (s, 1H), 7.23(tt, J = 20.6, 7.2 Hz, 5H), 4.08-3.93 (m, 2H), 3.79 (m 11H), 2.90-2.70(m, 2H), 1.83-1.69 (m, 1H), 1.40 (dd, J = 16.3, 9.3 Hz, 1H) - one peakis obscured by DMSO. 84 3 This spectrum contains some rotamers in thearomatic region: ¹H 498 NMR (400 MHz, DMSO-d6) δ 9.61, 9.49 (s, 1H),8.31, 8.27 (s, 2H), 8.14 (s, 1H), 7.91, 7.87 (s, 1H), 7.47 (s, 1H),7.35-7.11 (m, 6H), 4.06-3.91 (m, 3H), 3.81 (mz, 10H), 2.85-2.70 (m, 2H),1.76-1.53 (m, 3H), 1.41-1.27 (m, 1H). 85 3 This spectrum contains somerotamers in the aromatic region: ¹H 498 NMR (400 MHz, DMSO-d6) δ 9.61,9.49 (s, 1H), 8.3, 8.27 (s, 2H), 8.14 (s, 1H), 7.91, 7.87 (s, 1H), 7.46(d, J = 3.8 Hz, 1H), 7.32-7.25 (m, 2H), 7.25-7.15 (m, 3H), 4.05-3.92 (m,2H), 3.81 (m, 10H), 2.85-2.71 (m, 2H), 1.77-1.50 (m, 3H), 1.41-1.26 (m,1H) - a peak is partially obscured by water signal. 86 3 ¹H-NMR (400MHz, DMSO-d₆) δ ppm 9.65, 9.54 (s, s, 1H), 8.32 (s, 2H), 8.29, 8.16 (s,s, 1H), 7.89, 7.86 (s, s, 1H), 7.51, 7.47 (s, s, 1H), 7.31-7.17 (m, 5H),4.12-4.03 (m, 2H), 3.83-3.73 (m, 10H), 3.66-3.60 (m, 2H), 3.48-3.45 (m,2H), 2.72-2.63 (m, 1H), 1.93-1.87 (m, 1H), 1.62-1.55 (m, 1H). 87 3¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.65, 9.59 (s, s, 1H), 8.33-8.31 (m,2H), 8.16 (s, 1H), 7.87 (s, 1H), 7.50 (s, 1H), 7.34-7.18 (m, 5H), 4.59(d, 2H, J = 5.6 Hz), 4.35-4.22 (m, 4H), 3.85-3.75 (m, 10H), 1.13 (s,3H). 88 3 This spectrum contains some rotamers in the aromatic region:1H 500 NMR (400 MHz, DMSO-d6) δ 9.61, 9.48 (s, 1H), 8.31, 8.27 (s, 2H),8.14 (s, 1H), 7.83, 7.79 (s, 1H), 7.50, 7.45 (s, 1H), 7.32-7.13 (m, 5H),4.12-4.02 (m, 2H), 3.80 (d, J = 12.9 Hz, 10H), 2.13 (s, 8H), 1.93-1.80(m, 2H). 89 3 ¹H NMR (400 MHz, DMSO-d₆) δ 9.94 (s, 1H), 8.31 (d, J = 1.8Hz, 501 3H - actually two closely spaced singlets), 7.89-7.81 (m, 2H),7.68 (dd, J = 11.0, 8.4 Hz, 2H), 7.35-7.14 (m, 5H), 3.88-3.75 (m, 10H),1.62 (s, 3H), 1.59 (s, 3H). 91 1 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.66,9.60 (s, s, 1H), 8.52 (s, 2H), 8.24, 8.17 (s, s, 1H), 7.83 (s, 1H),7.50, 7.49 (s, s, 1H), 4.18-4.01 (m, 2H), 3.92-3.62 (m, 10H), 3.45-3.37(m, 1H), 2.75-2.56 (m, 3H), 2.39-2.28 (m, 1H). 92 2 ¹H-NMR (400 MHz,DMSO-d6) δ ppm 9.63 (br. s., 1H), 8.32 (s, 503 2H), 8.25 (s, 1H), 7.62(d, 2H, J = 8.8 Hz), 7.29-7.25 (m, 4H), 7.14-7.09 (m, 2H), 5.12 (d, 1H,J = 4.0 Hz), 4.68-4.65 (m, 1H), 4.50-4.46 (m, 1H), 3.83 (s, 5H), 3.79(s, 5H), 3.42-3.39 (m, 2H). 93 2 ¹H-NMR (400 MHz, DMSO-d6) δ ppm 9.62(br. s., 1H), 8.31 (s, 503 2H), 8.25 (s, 1H), 7.62 (d, 2H, J = 8.8 Hz),7.29-7.25 (m, 4H), 7.14-7.09 (m, 2H), 5.11 (br. s., 1H), 4.66 (br. s.,1H, J = 6.0 Hz), 4.50-4.46 (m, 1H), 3.84-3.79 (m, 10H), 3.42-3.40 (m,2H). 94 3 ¹H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.36 (s, 1H), 8.32(s, 2H), 8.02-7.93 (m, 2H), 7.89-7.81 (m, 2H), 7.34-7.14 (m, 5H), 3.85(br.s, 10H), 3.15 (s, 3H). 95 3 ¹H NMR (400 MHz, DMSO-d6) δ 10.05 (s,1H), 8.60 (s, 1H), 504 8.32 (s, 2H), 8.31 (s, 1H), 7.66 (d, J = 7.6 Hz,1H), 7.51-7.43 (m, 2H), 7.38-7.12 (m, 7H), 3.92-3.73 (m, 14H). 96 3 ¹HNMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.32 (s, 1H), 504 8.31 (s, 2H),7.91-7.84 (m, 2H), 7.78-7.71 (m, 2H), 7.32-7.14 (m, 7H), 3.92-3.68 (m,10H). 98 3 508 99 3 ¹H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.62 (s,2H), 508 8.37 (d, J = 12.4 Hz, 3H), 7.57-7.41 (m, 3H), 7.33-7.14 (m,5H), 4.23 (d, J = 4.5 Hz, 2H), 3.81 (m, 10H), 3.17 (dd, J = 6.8, 2.8 Hz,2H), 1.34 (s, 6H). 100 5 ¹H NMR (500 MHz, CDCl₃) δ ppm 8.46 (s, 2H),8.32, 8.22 (br. s., br. s., 1H), 7.87-7.50 (m, 2H), 7.30, 6.60 (br. s.,br. s., 1H), 7.21-7.16 (m, 1H), 7.09-7.01 (m, 3H), 4.24-4.14 (m, 2H),4.00-3.94 (m, 9H), 1.25 (d, 3H, J = 6.5 Hz). 102 3 ¹H NMR (400 MHz,DMSO-d6) δ 9.44 (s, 1H), 8.30 (s, 2H), 509 8.19 (s, 1H), 7.50 (d, J =8.5 Hz, 2H), 7.33-7.24 (m, 2H), 7.25-7.15 (m, 3H), 6.87 (d, J = 8.8 Hz,2H), 3.79 (br.s, 10H), 2.99 (dd, J = 6.5, 3.5 Hz, 4H), 2.85 (dd, J =6.3, 3.6 Hz, 4H). 103 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.30(s, 2H), 510 8.19 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.33-7.12 (m, 5H),6.90 (d, J = 8.6 Hz, 2H), 3.94-3.66 (m, 14H), 3.03 (t, J = 4.7 Hz, 4H).105 2 510 101 5 ¹H-NMR (500 MHz, CDCl₃) δ ppm 8.42 (s, 2H), 8.33, 8.22(br. s., br. s., 1H), 7.86-7.50 (m, 2H), 7.35, 6.62 (br. s., br. s.,1H), 7.21-7.18 (m, 2H), 6.98-6.95 (m, 2H), 4.24-4.13 (m, 2H), 4.00-3.93(m, 9H), 1.25 (d, 3H, J = 6.0 Hz). 104 3 ¹H NMR (400 MHz, DMSO-d6) δ9.53 (s, 1H), 8.31 (s, 2H), 510 8.24 (s, 1H), 7.44 (s, 1H), 7.32-7.05(m, 7H), 6.61 (d, J = 7.2 Hz, 1H), 3.86-3.71 (m, 14H), 3.07 (t, J = 4.8Hz, 4H). 106 2 510 107 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.30(s, 2H), 510 8.21 (s, 1H), 7.57 (d, J = 8.5 Hz, 2H), 7.35-7.12 (m, 5H),6.87 (d, J = 8.7 Hz, 2H), 4.87 (t, J = 5.6 Hz, 1H), 3.79 (m, 10H),3.20-3.11 (m, 2H), 3.07-2.89 (m, 3H), 2.12-1.97 (m, 1H), 1.91-1.80 (m,1H). 108 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.30 (s, 2H), 5108.20 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.34-7.12 (m, 5H), 6.84 (d, J =8.5 Hz, 2H), 4.85-4.68 (m, 1H), 3.79 (d, J = 5.8 Hz, 10H), 3.08-2.95 (m,1H), 2.94-2.69 (m, 3H), 2.04-1.91 (m, 1H), 1.79-1.67 (m, 1H). 109 1¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.52 (br. s., 1H), 8.26-8.25 (m, 3H),7.41-7.36 (m, 3H), 7.24-7.19 (m, 2H), 7.13-7.11 (m, 1H), 6.99 (d, 1H, J= 8.0 Hz), 5.14 (t, 1H, J = 5.5 Hz), 4.54 (d, 2H, J = 5.5 Hz), 3.85-3.78(m, 12H), 2.93 (t, 2H, J = 5.5 Hz), 2.62 (t, 2H, J = 5.5 Hz). 110 2¹H-NMR (500 MHz, CDCl₃) δ ppm 8.27 (s, 1H), 8.12 (s, 1H), 7.30-7.21 (m,4H), 7.11 (d, 2H, J = 7.5 Hz), 7.08 (d, 1H, J = 8.5 Hz), 6.93 (br. s.,1H), 4.50 (s, 2H), 4.02 (s, 2H), 3.92 (br. s., 8H), 3.75 (s, 2H), 3.15(t, 2H, J = 6.0 Hz), 2.78 (t, 2H, J = 5.5 Hz). 111 2 ¹H NMR (400 MHz,DMSO-d6) δ 9.33 (s, 1H), 8.31 (s, 2H), 510 8.17 (s, 1H), 7.44 (s, 2H),7.29 (t, J = 7.5 Hz, 2H), 7.26-7.16 (m, 3H), 6.48 (d, J = 8.3 Hz, 2H),4.92 (d, J = 3.9 Hz, 1H), 4.45-4.31 (m, 1H), 3.79 (d, J = 10.2 Hz, 10H),3.39 (dd, J = 10.0, 5.0 Hz, 1H), 3.23 (td, J = 8.6, 3.9 Hz, 1H), 3.04(d, J = 9.7 Hz, 1H), 2.03 (ddd, J = 13.2, 8.7, 5.0 Hz, 1H), 1.87 (ddt, J= 11.3, 7.0, 3.6 Hz, 1H) - appears to be one peak under water signal.112 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.31 (s, 2H), 510 8.17(s, 1H), 7.44 (s, 2H), 7.33-7.26 (m, 2H), 7.26-7.15 (m, 3H), 6.48 (d, J= 8.5 Hz, 2H), 4.92 (d, J = 3.8 Hz, 1H), 3.79 (d, J = 7.9 Hz, 10H), 3.39(dd, J = 10.0, 5.0 Hz, 1H), 3.26-3.18 (m, 1H), 3.04 (d, J = 10.0 Hz,1H), 2.11-1.97 (m, 1H), 1.87 (ddt, J = 11.4, 7.0, 3.7 Hz, 1H) - appearsto be one peak under the water signal. 113 1 ¹H-NMR (400 MHz, DMSO-d₆) δppm 9.53 (br, 1H), 8.27, 8.24 (s, s, 3H), 7.40 (s, 1H), 7.36 (d, 1H, J =8.4 Hz), 7.22-7.16 (m, 2H), 6.97 (t, 2H, J = 7.2 Hz), 6.88 (t, 1H, J =7.2 Hz), 3.79-3.72 (m, 16H), 2.92 (t, 2H, J = 5.6 Hz), 2.61 (t, 2H, J =5.6 Hz). 114 5 511 115 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.80 (br. s.,1H), 9.50-9.46 (br, 1H), 9.06 (s, 2H), 8.28 (s, 3H), 7.61 (s, 1H), 7.48(dd, 1H, J = 8.4, 2.0 Hz), 7.16 (d, 1H, J = 8.4 Hz), 7.08-7.00 (m, 2H),6.78 (d, 1H, J = 7.2 Hz), 6.73-6.69 (m, 1H), 4.27 (br. s., 2H),3.89-3.37 (m, 10H), 3.39-3.35 (m, 2H), 2.93 (t, 2H, J = 2.0 Hz). 16 3This spectrum contains some rotomers in the aromatic region: ¹H 512 NMR(400 MHz, DMSO-d6) δ 9.60, 9.49 (s, 1H), 8.30, 8.28 (s, 2H), 8.12, 8.14(s, 1H), 7.81, 7.77 (s, 1H), 7.48, 7.44 (s, 1H), 7.34-7.10 (m, 5H), 3.95(d, J = 7.2 Hz, 2H), 3.79 (t, J = 10.2 Hz, 10H), 2.76 (m, 2H), 2.23 (t,J = 10.6 Hz, 1H), 2.03-1.76 (m, 2H), 1.56 (br.s, 2H), 1.30 (m, 1H), 1.06(m, 1H). 117 3 This spectrum contains some rotamers in the aromaticregion: ¹H 512 NMR (400 MHz, DMSO-d6) δ 9.61, 9.48 (s, 1H), 8.30, 8.26(s, 2H), 8.14, 8.12 (s, 1H), 7.79, 7.78 (s, 1H), 7.49, 7.44 (s, 1H),7.34-7.09 (m, 5H), 4.17-3.98 (m, 2H), 3.79 (t, J = 12.4 Hz, 10H), 2.40(t, J = 6.9 Hz, 2H), 2.24, 2.15 (s, 3H), 1.85 (t, J = 6.7 Hz, 2H). 118 3¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.61, 9.50 (s, s, 1H), 8.32, 8.28 (s, s,2H), 8.15 (s, 1H), 7.85, 7.82 (s, s, 1H), 7.50, 7.47 (s, s, 1H), 7.29(t, 2H, J = 7.5 Hz), 7.23 (d, 2H, J = 7.5 Hz), 7.19 (t, 1H, J = 7.5 Hz),4.01-3.93 (m, 2H), 3.83-3.77 (m, 12H), 3.24 (t, 2H, J = 11.5 Hz), 2.01(br. s., 1H), 1.41-1.37 (m, 2H), 1.28-1.20 (m, 2H). 119 4 ¹H-NMR (400MHz, DMSO-d6) δ ppm 9.62 (br. s., 1H), 513 8.26-8.25 (m, 3H), 7.63 (d,2H, J = 8.8 Hz), 7.31-7.25 (m, 6H), 7.21-7.17 (m, 1H), 5.12 (d, 1H, J =4.0 Hz), 4.67-4.64 (m, 1H), 4.49-4.46 (m, 1H), 3.84 (br. s., 4H), 3.80(br. s., 4H), 3.42-3.39 (m, 2H), 1.64 (s, 6H). 120 4 ¹H-NMR (400 MHz,DMSO-d6) δ ppm 9.62 (br. s., 1H), 8.26, 513 8.25 (s, s, 3H), 7.63 (d,2H, J = 8.4 Hz), 7.33-7.17 (m, 7H), 5.11 (d, 1H, J = 4.4 Hz), 4.68-4.65(m, 1H), 4.49-4.48 (m, 1H), 3.85-3.80 (m, 8H), 3.43-3.40 (m, 2H), 1.64(s, 6H). 121 3 ¹H-NMR (400 MHz, DMSO-d6) δ ppm 10.02-9.96 (br, 1H), 5138.34, 8.33 (s, s, 3H), 7.57 (d, 2H, J = 8.4 Hz), 7.31-7.17 (m, 7H),4.76-4.41 (m, 4H), 4.28 (s, 1H), 3.86-3.80 (m, 8 H), 1.06 (s, 3H), 0.96(s, 3H). 122 3 ¹H-NMR (400 MHz, DMSO-d6) δ ppm 9.65 (br. s., 1H), 5138.32 (s, 2H), 8.26 (s, 1H), 7.59 (d, 2H, J = 8.4 Hz), 7.31-7.17 (m, 7H),5.10 (d, 1H, J = 3.6 Hz), 4.26 (d, 1H, J = 3.6 Hz), 4.21 (s, 1H),3.85-3.75 (m, 10H), 1.05 (s, 3H), 0.96 (s, 3H). 123 3 This spectrumcontains some rotamers in the aromatic region: ¹H 514 NMR (400 MHz,DMSO-d6) δ 9.62, 9.48 (s, 1H), 8.31, 8.27 (s, 2H), 8.14 (s, 1H), 7.81(s, 1H), 7.48, 7.45 (s, 1H), 7.33-7.12 (m, 4H), 4.21-3.98 (m, 2H), 3.80(d, J = 12.7 Hz, 10H), 2.84-2.57 (m, 3H), 2.41-2.26 (m, 1H) There is apeak partially obscured by water signal. 124 3 ¹H NMR (400 MHz, DMSO-d6)δ 9.63, 9.49 (s, 1H), 8.32, 8.28 (s, 514 2H), 8.15 (s, 1H), 7.82 (s,1H), 7.49, 7.47 (s, 1H), 7.34-7.26 (m, 2H), 7.26-7.15 (m, 3H), 4.13-4.01(m, 2H), 3.87-3.64 (m, 13H), 2.74-2.58 (m, 3H), 2.40-2.29 (m, 1H). 125 3This spectrum contains some rotamers in the aromatic region: 1H 514 NMR(400 MHz, DMSO-d6) δ 9.64, 9.51 (s, 1H), 8.31, 8.27 (s, 2H), 8.15 (s,1H), 7.84 (s, 1H), 7.51, 7.47 (s, 1H), 7.35-7.13 (m, 5H), 4.10-3.95 (m,2H), 3.81 (m, 10H), 3.68-3.55 (m, 2H), 3.17-3.00 (m, 2H), 2.81 (d, J =12.3 Hz, 1H), 2.70 (t, J = 11.7 Hz, 1H), 2.34 (d, J = 16.8 Hz, 1H). 1263 This spectrum contains some rotamers in the aromatic region: 1H 514NMR (400 MHz, DMSO-d6) δ 9.63, 9.51 (s, 1H), 8.31, 8.27 (s, 2H), 8.15(s, 1H), 7.84 (s, 1H), 7.50, 7.47 (s, 1H), 7.35-7.12 (m, 5H), 4.02 (d, J= 6.2 Hz, 2H), 3.81 (d, J = 13.9 Hz, 10H), 3.65-3.51 (m, 2H), 3.09 (t, J= 9.8 Hz, 1H), 3.00 (d, J = 8.4 Hz, 1H), 2.77 (d, J = 12.3 Hz, 1H), 2.68(d, J = 11.3 Hz, 1H), 2.34 (d, J = 16.8 Hz, 1H). 127 1 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.79 (br. s., 1H), 9.04 (br. s., 2H), 8.30 (s, 2H), 8.28(s, 1H), 7.61 (s, 1H), 7.48 (d, 1H, J = 9.6 Hz), 7.33-7.24 (m, 2H),7.18-7.12 (m, 3H), 4.27 (br. s., 2H), 3.82-3.80 (m, 10H), 3.39-3.35 (m,2H), 2.93 (t, 2H, J = 1.6 Hz). 128 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.93(s, 1H), 8.30 (d, J = 2.9 Hz, 515 2H), 7.90-7.81 (m, 2H), 7.68 (dd, J =11.1, 8.3 Hz, 2H), 7.33-7.14 (m, 5H), 4.98-4.82 (m, 1H), 4.69-4.38 (m,4H), 3.78 (s, 2H), 3.15 (s, 2H), 1.62, 1.59 (2 close singlets, 6H), 1.08(d, J = 6.9 Hz, 3H). 129 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H),8.32 (s, 2H), 515 8.22 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.37-7.08 (m,5H), 6.89 (d, J = 8.5 Hz, 2H), 4.92 (d, J = 4.9 Hz, 1H), 4.65 (t, J =5.6 Hz, 1H), 3.96 (dd, J = 9.5, 4.0 Hz, 1H), 3.80 (h, J = 5.6 Hz, 12H),3.44 (t, J = 5.5 Hz, 2H). 130 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.66 (s,1H), 8.30 (s, 3H), 515 7.48 (s, 1H), 7.40-7.04 (m, 8H), 3.89-3.88 (m,0H), 6.58 (d J = 7.9, 1H), 4.96 (s, 1H), 4.67 (s, 1H), 3.97 (dd, J =9.1, 3.7 Hz, 1H), 3.92-3.67 (m, 14H). 131 2 ¹H NMR (400 MHz, DMSO-d6) δ9.51 (s, 1H), 8.32 (s, 2H), 515 8.22 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H),7.37-7.08 (m, 5H), 6.89 (d, J = 8.5 Hz, 2H), 4.92 (d, J = 4.9 Hz, 1H),4.65 (t, J = 5.6 Hz, 1H), 3.96 (dd, J = 9.5, 4.0 Hz, 1H), 3.80 (h, J =5.6 Hz, 12H), 3.44 (t, J = 5.5 Hz, 2H). 132 2 ¹H NMR (400 MHz, DMSO-d6)δ 9.66 (s, 1H), 8.30 (s, 3H), 515 7.48 (s, 1H), 7.40-7.04 (m, 8H),3.89-3.88 (m, 0H), 6.58 (d J = 7.9, 1H), 4.96 (s, 1H), 4.67 (s, 1H),3.97 (dd, J = 9.1, 3.7 Hz, 1H), 3.92-3.67 (m, 14H). 133 3 ¹H NMR (400MHz, CDCl₃) δ ppm 8.21 (s, 3H), 7.76 (s, 1H), 7.57 (s, 1H), 7.32-7.28(m, 2H), 7.23-7.16 (m, 4H), 4.14-4.11 (m, 2H), 3.88 (br. s., 9H), 3.80(br. s., 4H), 3.72-3.69 (m, 2H), 3.62-3.55 (m, 1H), 3.33-3.28 (m, 1H).134 3 ¹H NMR (400 MHz, CDCl₃) δ ppm 8.21 (s, 3H), 7.75 (s, 1H), 7.59 (s,1H), 7.35-7.28 (m, 3H), 7.23-7.16 (m, 3H), 4.14-4.11 (m, 2H), 3.93-3.89(m, 9H), 3.81-3.69 (m, 6H), 3.61-3.55 (m, 1H), 3.33-3.27 (m, 1H). 135 5¹H NMR (400 MHz, DMSO-d₆) δ 9.64, 9.50 (s, 1H, rotamer), 8.31, 515 8.17(s, 3H, rotamer), 7.83 (s, 1H), 7.72 (s, 1H), 7.49 (s, 1H), 7.15 (t, J =7.8 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 6.71 (t, J = 7.5 Hz, 1H),4.14-4.00 (m, 2H), 3.87-3.64 (m, 10H), 3.47-3.35 (m, 1H), 2.75-2.66 (m,1H), 2.62 (d, J = 12.4 Hz, 2H), 2.41-2.30 (m, 1H). 136 1 ¹H-NMR (400MHz, DMSO-d₆ + 1d D₂O) δ ppm 8.26 (s, 2H), 8.25 (s, 1H), 7.63 (s, 1H),7.49 (s, 1H), 7.45 (d, 1H, J = 8.4 Hz), 7.41-7.31 (m, 1H), 7.13-7.09 (m,3H), 4.07 (s, 2H), 3.85-3.72 (m, 10H), 3.18 (d, 2H, J = 6.0 Hz), 2.83(t, 2H, J = 5.2 Hz). 137 1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.58 (br,1H), 8.32 (s, 2H), 8.25 (s, 1H), 7.43 (s, 1H), 7.38 (d, 1H, J = 8.0 Hz),7.33-7.26 (m, 1H), 7.21-7.09 (m, 2H), 7.01 (d, 1H, J = 8.4 Hz),3.92-3.77 (m, 13H), 2.97 (t, 2H, J = 6.0 Hz), 2.66 (t, 2H, J = 5.6 Hz).138 1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.55 (br, 1H), 8.30 (s, 2H), 8.24(s, 1H), 7.40-7.35 (m, 3H), 7.21 (t, 1H, J = 10.4 Hz), 7.04 (t, 1H, J =9.2 Hz), 6.98 (d, 1H, J = 8.0 Hz), 3.80 (br, 12H), 2.92 (t, 2H, J = 5.6Hz), 2.67-2.61 (m, 2H). 139 1 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.54 (br,1H), 8.33 (s, 2H), 8.23 (s, 1H), 7.42-7.29 (m, 4H), 7.10-7.07 (m, 1H),6.97 (d, 1H, J = 8.4 Hz), 3.80 (br, 13H), 2.91 (t, 2H, J = 5.6 Hz), 2.61(t, 2H, J = 5.2 Hz). 140 4 ¹H-NMR (400 MHz, DMSO-d6) δ ppm 9.65 (br. s.,1H), 8.39 (s, 516 2H), 8.26 (s, 1H), 7.63 (d, 2H, J = 8.4 Hz), 7.46 (dd,2H, J = 8.4, 5.6 Hz), 7.27 (d, 2H, J = 8.4 Hz), 7.13-7.08 (m, 2H), 5.06(d, 1H, J = 4.0 Hz), 4.70-4.64 (m, 1H), 3.85-3.70 (m, 8H), 3.45-3.25 (m,2H), 1.73 (s, 3H), 1.31 (d, 3H, J = 6.4 Hz). 141 1 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 9.66, 9.52 (s, s, 1H), 8.33 (s, 2H), 8.29, 8.16 (s, s,1H), 7.83 (s, 1H), 7.50, 7.48 (s, s, 1H), 7.31-7.18 (m, 5H), 4.12-4.03(m, 2H), 3.84-3.66 (m, 11H), 2.72-2.60 (m, 3H), 2.38-2.33 (m, 1H). 142 1¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.01, 8.77 (s, s, 1H), 8.50 (s, 2H),8.16, 8.14 (s, s, 1H), 7.55, 7.41 (s, s, 1H), 4.02-3.96 (m, 2H),3.82-3.64 (m, 10H), 3.34 (br, 2H), 2.73-2.71 (m, 1H), 2.63-2.59 (m, 2H),2.41-2.36 (m, 1H), 2.17, 2.12 (s, s, 3H). 143 1 ¹H NMR (400 MHz,DMSO-d6) δ 10.17 (s, 1H), 8.35 (s, 1H), 519 7.99-7.92 (m, 2H), 7.88-7.81(m, 2H), 7.63 (s, 1H), 7.28-7.18 (m, 4H), 7.18-7.11 (m, 1H), 3.83 (s,4H), 3.68 (s, 4H), 3.56 (s, 2H), 3.15 (s, 3H). 145 3 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 9.56 (br. s., 1H), 8.32 (s, 2H), 8.24 (s, 1H), 7.42-7.40(m, 2H), 7.29 (t, 2H, J = 7.5 Hz), 7.23 (d, 2H, J = 7.0 Hz), 7.20 (t,1H, J = 7.5 Hz), 7.01 (d, 1H, J = 8.0 Hz), 3.82-3.80 (m, 10H), 3.67 (s,2H), 2.82 (t, 2H, J = 5.5 Hz), 2.71 (t, 2H, J = 5.5 Hz), 1.88-1.77 (m,1H), 0.51-0.47 (m, 2H), 0.41-0.38 (m, 2H). 148 3 ¹H NMR (400 MHz,DMSO-d6) δ 9.54, 9.49 (s, 1H), 8.31, 8.27 (s, 522 2H), 8.24 (s, 1H),7.40 (d, J = 8.2 Hz, 2H), 7.33-7.26 (m, 2H), 7.25-7.16 (m, 3H), 7.01 (d,J = 8.3 Hz, 1H), 3.85-3.76 (m, 10H), 3.59 (s, 2H), 2.90-2.82 (m, 1H),2.69 (d, J = 16.3 Hz, 4H), 1.05 (d, J = 6.4 Hz, 6H). 149 5 ¹H-NMR (500MHz, DMSO-d₆) δ ppm 9.68, 9.55 (s, s, 1H), 8.54 (s, 2H), 8.30, 8.17 (s,s, 1H), 7.96, 7.88 (s, s, 1H), 7.47-7.46 (m, 1H), 7.27-7.25 (m, 2H),7.19-7.16 (m, 2H), 4.73, 4.67 (s, s, 1H), 3.95-3.88 (m, 10H), 1.06-1.05(m, 6H). 150 5 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.70, 9.58 (s, s, 1H),8.56 (s, 2H), 8.31, 8.18 (s, s, 1H), 7.96, 7.88 (s, s, 1H), 7.48-7.46(m, 1H), 7.28-7.26 (m, 2H), 7.17-7.14 (m, 1H), 7.04-7.01 (m, 1H), 4.75,4.68 (s, s, 1H), 4.00-3.89 (m, 10H), 1.06-1.05 (m, 6H). 155 2 ¹H-NMR(400 MHz, CDCl₃) δ ppm 8.28 (s, 1H), 8.20 (s, 2H), 7.53 (d, 2H, J = 8.4Hz), 7.48 (d, 2H, J = 8.4 Hz), 7.32-7.26 (m, 2H), 7.23-7.16 (m, 3H),3.91-3.88 (m, 8H), 3.81 (s, 2H), 1.88-1.71 (m, 8H), 1.65-1.62 (m, 1H),1.34-1.25 (m, 1H). 156 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.30(s, 2H), 523 8.19 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.34-7.13 (m, 5H),6.89 (d, J = 8.6 Hz, 2H), 3.89-3.66 (m, 10H), 3.07 (t, J = 4.9 Hz, 4H),2.23 (s, 3H) - one peak is obscured by water signal. 157 2 ¹H NMR (400MHz, DMSO-d6) δ 9.51 (s, 1H), 8.31 (s, 2H), 523 8.24 (s, 1H), 7.43 (s,1H), 7.31-7.03 (m, 7H), 6.64-6.56 (m, 1H), 3.98-3.65 (m, 12H), 3.11 (t,J = 4.9 Hz, 4H), 2.24 (s, 3H). 158 3 ¹H NMR (400 MHz, DMSO-d6) δ 8.77(s, 1H), 8.29 (s, 2H), 523 8.10 (s, 1H), 7.28 (t, J = 7.5 Hz, 2H),7.25-7.12 (m, 4H), 6.81-6.69 (m, 2H), 3.75 (m, 10H), 3.03 (dd, J = 6.6,3.5 Hz, 4H), 2.85 (dd, J = 6.2, 3.6 Hz, 4H), 2.12 (s, 3H). 159 3 ¹H NMR(400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.31 (s, 2H), 524 8.23 (s, 1H), 7.53(d, J = 8.2 Hz, 2H), 7.35-7.11 (m, 5H), 6.95 (d, J = 8.5 Hz, 2H), 4.87(br.s, 1H), 4.58 (br.s, 1H), 4.46 (t, J = 15.2 Hz, 4H), 3.78 (s, 2H),3.77-3.69 (m, 4H), 3.26 (m, 1H), 3.11-3.03 (m, 4H), 1.05 (d, J = 6.4 Hz,3H). 160 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.31 (d, J = 1.3Hz, 524 2H), 8.25 (s, 1H), 7.79 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H),7.36-7.13 (m, 6H), 6.98-6.87 (m, 1H), 3.89-3.73 (m, 10H), 3.64-3.52 (m,4H), 3.42 (s, 2H), 2.42-2.28 (m, 9H). 161 2 ¹H NMR (400 MHz, DMSO-d6) δ9.51 (s, 1H), 8.30 (s, 2H), 524 8.21 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H),7.33-7.24 (m, 2H), 7.24-7.15 (m, 3H), 6.90 (d, J = 9.0 Hz, 2H),4.25-4.18 (m, 1H), 3.78 (br.s, J = 6.9 Hz, 10H), 3.15-3.05 (m, 1H),2.86-2.74 (m, 1H), 2.62-2.54 (m, 1H), 2.05-1.91 (m, 2H), 1.72-1.65 (m,1H), 1.56-1.36 (m, 2H). This spectra has slight evidence of rotamers inthe aromatic region. 162 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H),8.30 (s, 2H), 524 8.21 (s, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.33-7.24 (m,2H), 7.24-7.15 (m, 3H), 6.90 (d, J = 9.0 Hz, 2H), 4.25-4.18 (m, 1H),3.78 (br.s, J = 6.9 Hz, 10H), 3.15-3.05 (m, 1H), 2.86-2.74 (m, 1H),2.62-2.54 (m, 1H), 2.05-1.91 (m, 2H), 1.72-1.65 (m, 1H), 1.56-1.36 (m,2H). This spectra has slight evidence of rotamers in the aromaticregion. 163 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.74 (s, 1H),524 8.31 (s, 2H), 8.27 (s, 1H), 7.58 (s, 1H), 7.56-7.50 (m, 1H),7.32-7.25 (m, 2H), 7.25-7.11 (m, 4H), 5.42-5.28 (m, 1H), 4.59-4.25 (m,4H), 3.92-3.71 (m, 12H), 3.09-2.94 (m, 2H). 164 3 ¹H NMR (400 MHz,DMSO-d6) δ 9.62 (s, 1H), 8.39-8.06 (m, 524 3H), 7.62-6.91 (m, 7H), 4.93(d, J = 23.8 Hz, 2H), 4.58 (dd, J = 29.9, 13.0 Hz, 4H), 4.02 (s, 2H),3.78 (s, 2H), 3.57-2.85 (m, 3H), 2.76 (t, J = 5.8 Hz, 2H), 1.64 (bs,2H). 165 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.30 (s, 2H), 5248.19 (s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.78(s, 1H), 3.79 (p, J = 7.1 Hz, 10H), 3.62-3.54 (m, 1H), 3.51 (dd, J =11.7, 4.0 Hz, 1H), 2.64-2.54 (m, 2H), 2.48-2.37 (m, 1H), 1.86 (dt, J =12.1, 4.1 Hz, 1H), 1.73 (dt, J = 13.5, 3.8 Hz, 1H), 1.60-1.44 (m, 2H),1.30-1.16 (m, 2H); one signal is partially obscured by water peak. 166 2¹H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.30 (s, 2H), 524 8.19 (s,1H), 7.49 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.77 (s, 1H),3.65-3.43 (m, 2H), 2.57 (t, J = 10.7 Hz, 1H), 2.42 (t, J = 10.2 Hz, 1H),1.87 (dq, J = 12.6, 4.3 Hz, 1H), 1.73 (dt, J = 13.2, 3.8 Hz, 1H),1.62-1.44 (m, 1H), 1.31-1.15 (m, 2H). 167 2 ¹H NMR (400 MHz, DMSO-d6) δ9.32 (s, 1H), 8.30 (s, 2H), 524 8.15 (s, 1H), 7.43 (s, 2H), 7.34-7.12(m, 5H), 6.55 (d, J = 8.5 Hz, 2H), 4.70 (dd, J = 6.3, 5.1 Hz, 1H), 3.78(m, 10H), 3.60 (dt, J = 8.4, 4.5 Hz, 1H), 3.48 (dt, J = 9.3, 4.4 Hz,1H), 3.15 (ddd, J = 10.7, 8.6, 6.5 Hz, 1H), 3.04-2.92 (m, 1H), 2.04-1.77(m, 4H) - one peak is obscured by water signal. 168 2 ¹H NMR (400 MHz,DMSO-d6) δ 9.32 (s, 1H), 8.30 (s, 2H), 524 8.15 (s, 1H), 7.43 (s, 2H),7.35-7.13 (m, 5H), 6.55 (d, J = 8.5 Hz, 2H), 4.70 (dd, J = 6.4, 5.1 Hz,1H), 3.78 (m, 10H), 3.66-3.56 (m, 2H), 3.48 (dt, J = 9.5, 4.4 Hz, 1H),3.20-3.09 (m, 1H), 3.04-2.91 (m, 2H), 2.04-1.81 (m, 4H) one peak isobscured by water signal. 169 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.50 (s,1H), 8.30 (s, 2H), 524 8.21 (s, 1H), 7.61-7.50 (m, 2H), 7.34-7.12 (m,5H), 6.87 (d, J = 8.7 Hz, 2H), 3.87-3.69 (m, 10H), 2.86-2.72 (m, 2H),1.88-1.76 (m, 1H), 1.74-1.55 (m, 2H), 1.49-1.35 (m, 1H) - one peakobscured by water signal. 170 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.50 (s,1H), 8.30 (s, 2H), 524 8.21 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.34-7.12(m, 4H), 6.87 (d, J = 8.7 Hz, 2H), 3.87-3.69 (m, 10H), 2.86-2.73 (m,2H), 1.89-1.75 (m, 1H), 1.74-1.55 (m, 2H), 1.49-1.35 (m, 1H) - one peakobscured by water signal. 171 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.60 (s,1H), 8.35 (s, 1H), 525 8.32 (s, 2H), 8.24 (s, 1H), 7.94 (dd, J = 8.9,2.7 Hz, 1H), 7.36-7.15 (m, 5H), 6.75 (d, J = 8.9 Hz, 1H), 4.84 (dt, J =8.9, 4.7 Hz, 1H), 3.79 (d, J = 5.4 Hz, 10H), 3.11 (dd, J = 12.0, 3.9 Hz,1H), 2.77 (dt, J = 12.2, 4.0 Hz, 1H), 2.04 (d, J = 11.0 Hz, 1H), 1.66(dt, J = 12.5, 4.3 Hz, 1H), 1.57-1.37 (m, 2H) - one peak obscured byDMSO signal. 172 3 ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 8.32(s, 2H), 525 8.26 (s, 1H), 7.65 (s, 1H), 7.63 (d, 1H, J = 8.4 Hz),7.33-7.15 (m, 7H), 5.48 (d, 1H, J = 3.6 Hz), 4.77-4.65 (m, 3H), 4.10 (d,1H, J = 5.2 Hz), 4.01 (d, 1H, J = 5.2 Hz), 3.88-3.70 (m, 10H), 1.11 (s,3H). 173 4 ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.67, 9.54 (s, s, 1H), 8.34(s, 2H), 8.30, 8.17 (s, s, 1H), 7.83 (s, 1H), 7.50, 7.47 (s, s, 1H),7.41-7.34 (m, 5H), 5.51 (s, 1H), 5.43 (s, 1H), 4.12-4.03 (m, 2H),3.91-3.87 (m, 8H), 3.72-3.66 (m, 2H), 3.41-3.37 (m, 1H), 2.72-2.59 (m,3H), 2.37-2.33 (m, 2H). 174 3 rotamers in aromatic region: 1H NMR (400MHz, DMSO-d6) δ 526 9.60 (s, 1H), 8.31 (s, 2H), 8.14 (s, 1H), 7.82, 7.80(s, 1H), 7.47, 7.45 (s, 1H), 7.33-7.13 (m, 5H), 4.04-3.89 (m, 2H), 3.80(m, 8H), 2.76 (m, 2H), 2.16 (s, 3H), 1.85 (m, 2H), 1.75 (m, 1H), 1.43(m, 2H), 1.21 (m, 2H). 175 3 527 176 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm9.66, 9.53 (s, s, 1H), 8.32 (s, 2H), 8.29, 8.15 (s, s, 1H), 7.87, 7.85(s, s, 1H), 7.46 (s, 1H), 7.31-7.17 (m, 5H), 4.31-4.12 (m, 2H),3.99-3.79 (m, 11H), 2.69-2.55 (m, 3H), 2.29-2.22 (m, 5H), 2.10-2.05 (m,1H). 177 3 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.67, 9.54 (s, s, 1H),8.31-8.28 (m, 2H), 8.15 (s, 1H), 7.88 (s, 1H), 7.47 (s, 1H), 7.30-7.17(m, 5H), 4.32-4.22 (m, 2H), 3.83-3.79 (m, 11H), 2.84-2.64 (m, 4H),2.44-2.28 (m, 5H), 2.18-2.13 (m, 1H). 178 4 ¹H-NMR (500 MHz, DMSO-d₆) δppm 9.70, 9.57 (s, s, 1H), 8.77 (s, 2H), 8.32, 8.19 (s, s, 1H), 7.84 (s,1H), 7.75 (d, 2H, J = 7.5 Hz), 7.69 (t, 1H, J = 7.5 Hz), 7.58 (t, 2H, J= 8.0 Hz), 7.51, 7.48 (s, s, 1H), 4.16-3.95 (m, 6H), 3.93-3.87 (m, 4H),3.73-3.64 (m, 2H), 3.39-3.31 (m, 1H), 2.72-2.55 (m, 3H), 2.38-2.34 (m,2H). 179 1 528 180 3 This spectrum contains some rotomers in thearomatic region: ¹H 528 NMR (400 MHz, DMSO-d6) δ 9.63, 9.51 (s, 1H),8.31, 8.27 (s, 2H), 8.15 (s, 1H), 7.83 (s, 1H), 7.49 (s, 1H), 7.34-7.14(m, 5H), 4.20-4.08 (m, 2H), 3.79 (s, 10H), 3.58-3.41 (m, 2H), 2.29-2.09(m, 3H) - some peaks are partially obscured by water signal. 181 3 Thisspectrum contains some rotomers in the aromatic region: ¹H 528 NMR (300MHz, DMSO-d6) δ 9.65, 9.51 (s, 1H), 8.32, 8.28 (s, 2H), 8.16 (s, 1H),7.84 (s, 1H), 7.50 (s, 1H), 7.35-7.13 (m, 5H), 4.22-4.04 (m, 2H), 3.81(d, J = 9.4 Hz, 10H), 3.46 (m, 1H), 2.58 (t, J = 11.8 Hz, 2H), 2.15 (s,3H), 2.03-1.87 (m, 2H), 1.72 (t, J = 10.6 Hz, 2H). 182 3 ¹H NMR (400MHz, DMSO-d6) δ 9.65, 9.63 (s, 1H), 8.30, 8.31 (s, 528 2H), 8.14 (d, J =2.9 Hz, 1H), 7.91 (s, 1H), 7.46, 7.43 (s, 1H), 7.34-7.10 (m, 5H),4.09-3.93 (m, 2H), 3.90-3.67 (m, 10H), 2.90-2.69 (m, 2H), 2.33-2.23 (m,2H), 1.52-1.24 (m, 4H). 183 3 This spectrum contains some rotomers inthe aromatic region: ¹H 528 NMR (400 MHz, DMSO-d6) δ 9.62, 9.46 (s, 1H),8.30, 8.26 (s, 2H), 8.14 (s, 1H), 7.82 (d, J = 2.7 Hz, 1H), 7.46 (s,1H), 7.35-7.12 (m, 4H), 5.01-4.38 (m, 5H), 4.16-3.96 (m, 2H), 3.78 (s,2H), 3.75-3.60 (m, 2H), 3.38 (dd, J = 11.6, 8.3 Hz, 1H), 3.21-2.99 (m,2H), 2.76-2.56 (m, 3H), 2.40-2.27 (m, 1H), 1.05 (d, J = 6.4 Hz, 3H). 1843 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.06, 8.79 (s, s, 1H), 8.32 (s, 2H),8.18, 8.16 (s, s, 1H), 7.79, 7.70 (s, s, 1H), 7.29 (t, 2H, J = 9.0 Hz),7.24-7.17 (m, 3H), 4.03-3.94 (m, 2H), 3.79-3.63 (m, 7H), 3.43-3.38 (m,1H), 2.83-2.56 (m, 3H), 2.38-2.32 (m, 1H), 2.12, 2.07 (s, s, 3H). 185 3¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.97, 8.73 (s, s, 2H), 8.30, 8.14 (s, s,3H), 7.54, 7.40 (s, s, 1H), 7.31-7.17 (m, 4H), 4.02-3.98 (m, 2H),3.79-3.64 (m, 10H), 3.78-3.35 (m, 1H), 2.74-2.59 (m, 4H), 2.49-2.36 (m,2H), 2.16-2.12 (m, 3H). 186 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.62, 9.50(s, s, 1H), 8.32-8.14 (m, 3H), 7.83-7.81 (m, 1H), 7.48-7.46 (m, 1H),7.29-7.16 (m, 5H), 4.10-4.02 (m, 3H), 3.82-3.64 (m, 11H), 2.71-2.58 (m,3H), 2.49-2.33 (m, 1H), 1.56 (d, 3H, J = 7.2 Hz). 187 5 511 188 3 ¹H NMR(400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.31 (s, 2H), 530 8.26 (s, 1H), 7.76(s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.35-7.12 (m, 6H), 6.92 (d, J = 7.5Hz, 1H), 3.94-3.51 (m, 16H). 189 4 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.66,9.52 (s, s, 1H), 8.33 (s, 2H), 8.28, 8.16 (s, s, 1H), 7.83 (s, 1H),7.49, 7.47 (s, s, 1H), 7.39 (d, 2H, J = 7.5 Hz), 7.34 (t, 2H, J = 7.5Hz), 7.24 (t, 1H, J = 7.0 Hz), 5.96 (d, 1H, J = 4.5 Hz), 5.66 (d, 1H, J= 4.0 Hz), 4.14-4.02 (m, 2H), 3.85-3.75 (m, 8H), 3.73-3.62 (m, 2H),3.41-3.39 (m, 1H), 2.71-2.55 (m, 3H), 2.35-2.31 (m, 2H). 190 2 ¹H NMR(400 MHz, DMSO-d6) δ 9.64, 9.51 (s, 1H, rotamer), 530 8.51 (s, 2H), 7.83(s, 1H), 8.17 (s, 1H) 7.49 (s, 1H), 7.35-7.26 (m, 2H), 7.05-6.91 (m,3H), 4.96 (s, 2H), 4.10-4.03 (m, 2H), 3.86 (m, 8H), 3.76-3.64 (m, 2H),3.45-3.27 (m, 1H), 2.70-2.62 (m, 3H), 2.41-2.30 (m, 2H). 191 3 Thisspectrum contains some rotomers in the aromatic region: ¹H 530 NMR (400MHz, DMSO-d6) δ 9.65, 9.53 (s, 1H), 8.31, 8.28 (s, 2H), 8.15 (s, 1H),7.84 (s, 1H), 7.50, 7.48 (s, 1H), 7.32-7.13 (m, 5H), 4.32 (d, J = 21.6Hz, 2H), 3.79 (m, 10H), 2.84-2.60 (m, 4H), 1.67-1.43 (m, 4H). 192 3¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.75 (br. s., 1H), 8.33 (s, 2H), 8.29(s, 1H), 7.63 (s, 1H), 7.54 (dd, 1H, J = 8.0, 1.5 Hz), 7.37 (br. s.,1H), 7.30 (t, 2H, J = 7.5 Hz), 7.24 (d, 2H, J = 7.5 Hz), 7.20 (t, 1H, J= 7.0 Hz), 7.08 (d, 1H, J = 8.5 Hz), 4.42 (s., 2H), 4.31 (s, 2H),3.88-3.75 (m, 10H). 193 4 ¹H-NMR (400 MHz, DMSO-d6) δ ppm 9.63 (br. s.,1H), 8.39 (s, 530 2H), 8.25 (s, 1H), 7.61 (d, 2H, J = 8.4 Hz), 7.46 (dd,2H, J = 8.4, 5.6 Hz), 7.39 (d, 2H, J = 8.8 Hz), 7.13-7.08 (m, 2H), 4.93(s, 1H), 3.85-3.70 (m, 8H), 2.67-2.64 (m, 2H), 1.73 (s, 3H), 1.41 (s,6H). 194 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.64, 9.49 (s, br. s., 1H),8.28, 8.14 (s, s, 1H), 7.96 (s, 1H), 7.83 (br. s., 1H), 7.48 (br. s.,1H), 6.80-6.75 (br, 1H), 4.91-4.80 (m, 1H), 4.76-4.45 (m, 3H), 4.09-3.99(m, 2H), 3.75-3.63 (m, 2H), 3.26-2.99 (m, 4H), 2.72-2.62 (m, 3H),2.42-2.33 (m, 2H), 1.04 (br. s., 3H). 195 4 ¹H-NMR (400 MHz, DMSO-d6) δppm 9.67 (s, 1H), 8.39 (s, 2H), 532 8.26 (s, 1H), 7.63 (d, 2H, J = 8.0Hz), 7.48-7.44 (m, 2H), 7.26 (d, 2H, J = 8.0 Hz), 7.13-7.09 (m, 2H),5.16 (d, 1H, J = 4.0 Hz), 4.71 (t, 1H, J = 5.6 Hz), 4.50-4.46 (m, 1H),3.83-3.82 (m, 8H), 3.42-7.39 (m, 2H), 2.50 (s, 3H), 1.72 (s, 3H). 196 1¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.63, 9.50 (s, s, 1H), 8.32-8.16 (m,3H), 7.82 (s, 1H), 7.49-7.47 (m, 1H), 7.29-7.26 (m, 2H), 7.14-7.09 (m,2H), 4.11-4.02 (m, 2H), 3.83-3.65 (m, 12H), 3.42-3.39 (m, 1H), 2.71-2.59(m, 3H), 2.38-2.32 (m, 1H). 197 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.64,9.50 (s, s, 1H), 8.34-8.16 (m, 3H), 7.83 (s, 1H), 7.50-7.47 (m, 1H),7.36-7.30 (m, 1H), 7.11-7.00 (m, 3H), 4.10-4.03 (m, 2H), 3.83-3.65 (m,12H), 3.39-3.33 (m, 1H), 2.71-2.60 (m, 3H), 2.38-2.33 (m, 1H). 198 1¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.64, 9.50 (s, s, 1H), 8.30 (s, 2H),8.16 (s, 1H), 7.83 (s, 1H), 7.49-7.47 (m, 1H), 7.34-7.26 (m, 2H),7.19-7.13 (m, 2H), 4.11-4.03 (m, 2H), 3.83-3.66 (m, 12H), 3.42-3.34 (m,1H), 2.71-2.50 (m, 3H), 2.38-2.32 (m, 1H). 199 5 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 9.67, 9.54 (s, s, 1H), 8.54 (s, 2H), 8.30, 8.17 (s, s,1H), 7.83 (s, 1H), 7.50, 7.47 (s, s, 1H), 7.33-7.30 (m, 2H), 7.21-7.16(m, 3H), 4.14-4.03 (m, 2H), 3.94-3.88 (m, 8H), 3.72-3.64 (m, 2H),3.41-3.36 (m, 1H), 2.71-2.58 (m, 3H), 2.37-2.31 (m, 1H). 200 5 1H NMR(400 MHz, DMSO-d6) δ 9.50, 9.64 (s, 1H, rotamer), 533 8.29, 8.17 (s, 2H,rotamer), 7.83 (s, 1H), 7.68 (s, 1H), 7.48, 7.51 (s, 1H, rotamer), 7.00(t, J = 8.8 Hz, 2H), 6.80 (dd, J = 8.9, 4.6 Hz, 2H), 4.23-3.50 (m, 12H),3.49-3.37 (m, 2H), 2.82-2.55 (m, 3H), 2.42-2.17 (m, 2H). 201 4 ¹H-NMR(400 MHz, CD3OD) δ ppm 8.23 (s, 2H), 8.13 (s, 1H), 533 8.05 (s, 1H),7.56 (s, 1H), 7.32-7.29 (m, 2H), 7.06-7.01 (m, 2H), 4.09-4.06 (m, 2H),3.93-3.87 (m, 8H), 1.68 (3, 3H), 1.19 (s, 3H). 202 5 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 9.64, 9.50 (s, s, 1H), 8.34 (s, 2H), 8.29, 8.16 (s, s,1H), 7.82 (s, 1H), 7.50, 7.49 (s, s, 1H), 7.20-7.16 (m, 2H), 7.05-7.01(m, 2H), 4.10-4.00 (m, 2H), 3.86-3.78 (m, 8H), 3.75-3.61 (m, 2H),3.47-3.36 (m, 1H), 2.71-2.62 (m, 3H), 2.40-2.30 (m, 1H). 203 5 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 9.65, 9.52 (s, s, 1H), 8.37 (s, 2H), 8.28, 8.16(s, s, 1H), 7.82 (s, 1H), 7.50, 7.46 (s, s, 1H), 7.39-7.33 (m, 1H),7.16-7.11 (m, 2H), 7.06-7.02 (m, 1H), 4.18-4.01 (m, 2H), 3.86-3.80 (m,8H), 3.71-3.65 (m, 2H), 3.39-3.37 (m, 2H), 2.71-2.56 (m, 3H), 2.34-2.30(m, 1H). 204 5 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.64, 9.52 (br. s., br.s., 1H), 8.38 (s, 2H), 8.32, 8.16 (s, s, 1H), 7.82 (s, 1H), 7.50, 7.48(s, 1H), 7.39-7.35 (m, 1H), 6.95-6.85 (m, 2H), 6.81 (dd, 1H, J = 8.0,2.0 Hz), 4.10-4.06 (m, 2H), 3.87-3.82 (m, 8H), 3.76-3.61 (m, 2H),3.45-3.35 (m, 1H), 2.66-2.62 (m, 3H), 2.41-2.29 (m, 1H). 205 5 ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 10.14 (br. s., 1H), 8.56 (s, 2H), 8.36 (s, 1H),7.77-7.75 (m, 2H), 7.42-7.40 (m, 2H), 7.28-7.25 (m, 2H), 7.18-7.14 (m,1H), 7.07-7.03 (m, 1H), 3.91 (br. s., 10H), 3.25-3.23 (m, 1H), 3.12-3.06(m, 1H), 1.13 (d, 3H, J = 6.0 Hz). 206 5 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm10.08 (br. s., 1H), 8.56 (s, 2H), 8.35 (s, 1H), 7.77-7.75 (m, 2H),7.36-7.25 (m, 4H), 7.18-7.14 (m, 1H), 7.06-7.03 (m, 1H), 3.91 (br. s.,10H), 3.25-3.22 (m, 1H), 3.11-3.06 (m, 1H), 1.13 (d, 3H, J = 6.0 Hz).207 4 ¹H-NMR (400 MHz, DMSO-d6) δ ppm 9.66, 9.53 (s, s, 1H), 535 8.39(s, 2H), 8.30, 8.16 (s, s, 1H), 7.94, 7.87 (s, s, 1H), 7.48-7.44 (m,3H), 7.15-7.10 (m, 2H), 5.89 (s, 1H), 4.73, 4.67 (s, s, 1H), 4.00, 3.94(s, s, 2H), 3.83-3.79 (m, 8H), 1.81 (s, 3H), 1.06 (s, 6H). 208 4 ¹H-NMR(400 MHz, DMSO-d6) δ ppm 9.66, 9.52 (s, s, 1H), 535 8.39 (s, 2H), 8.28,8.15 (s, s, 1H), 7.93, 7.86 (s, s, 1H), 7.47-7.43 (m, 3H), 7.15-7.01 (m,2H), 5.89 (s, 1H), 4.73, 4.67 (s, s, 1H), 4.00, 3.94 (s, s, 2H),3.82-3.78 (m, 8H), 1.81 (s, 3H), 1.06 (s, 6H). 211 3 537 212 3 ¹NMR (400MHz, DMSO-d6) δ 8.77 (s, 1H), 8.29 (s, 2H), 537 8.09 (s, 1H), 7.32-7.24(m, 2H), 7.24-7.12 (m, 4H), 6.80-6.68 (m, 2H), 3.75 (m, 10H), 3.13-3.03(m, 4H), 2.43 (t, J = 5.0 Hz, 4H), 2.21 (s, 3H), 2.12 (s, 3H). 215 3 ¹HNMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.30 (s, 2H), 538 8.23 (s, 1H),7.39 (d, J = 9.4 Hz, 1H), 7.33-7.13 (m, 6H), 7.00 (d, J = 8.1 Hz, 1H),3.80 (d, J = 8.1 Hz, 10H), 3.60-3.47 (m, 4H), 3.29 (s, 4H), 3.26 (s,3H), 2.76-2.59 (m, 4H). 216 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H),8.30 (s, 2H), 538 8.21 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.34-7.13 (m,5H), 6.90 (d, J = 8.5 Hz, 2H), 4.34-4.27 (m, 1H), 3.79 (m, 10H),2.91-2.83 (m, 1H), 2.61-2.52 (m, 1H), 2.20 (s, 3H), 2.08-1.87 (m, 3H),1.75-1.67 (m, 1H), 1.58-1.49 (m, 1H), 1.37-1.28 (m, 1H). 217 2 ¹H NMR(400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.30 (s, 2H), 538 8.21 (s, 1H), 7.55(d, J = 8.6 Hz, 2H), 7.34-7.13 (m, 5H), 6.90 (d, J = 8.5 Hz, 2H),4.34-4.27 (m, 1H), 3.79 (m, 10H), 2.91-2.83 (m, 1H), 2.61-2.52 (m, 1H),2.20 (s, 3H), 2.08-1.87 (m, 3H), 1.75-1.67 (m, 1H), 1.58-1.49 (m, 1H),1.37-1.28 (m, 1H). 218 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.30(s, 2H), 538 8.21 (s, 1H), 7.55 (d, J = 8.7 Hz, 2H), 7.34-7.14 (m, 5H),6.89 (d, J = 8.5 Hz, 2H), 3.94 (dd, J = 9.6, 5.4 Hz, 1H), 3.79 (d, J =3.9 Hz, 10H), 2.97 (br.s, 1H), 2.37 (s, 3H), 2.21 (br.s, 1H), 2.03-1.88(m, 1H), 1.76-1.63 (m, 2H), 1.64-1.51 (m, 1H) - a peak is obscured bythe water signal. 219 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.30(s, 2H), 538 8.21 (s, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.35-7.12 (m, 5H),6.89 (d, J = 8.5 Hz, 2H), 3.94 (dd, J = 9.6, 5.4 Hz, 1H), 3.79 (d, J =6.6 Hz, 10H), 2.98 (br.s, 1H), 2.38 (br.s, 3H), 2.22 (s, 1H), 2.03-1.89(m, 1H), 1.77-1.64 (m, 2H), 1.64-1.53 (m, 1H) a peak is obscured by thewater signal. 220 3 ¹H-NMR (500 MHz, CD₃OD) δ ppm 8.25 (s, 2H), 8.19 (s,1H), 7.38 (d, 1H, J = 8.0 Hz), 7.37 (s, 1H), 7.32 (d, 1H, J = 8.0 Hz),7.31 (d, 1H, J = 8.0 Hz), 7.24-7.20 (m, 3H), 7.10 (d, 1H, J = 8.0 Hz),4.64 (s, 2H), 4.11-4.06 (m, 1H), 3.93-3.90 (m, 4H), 3.87-3.84 (m, 6H),3.78-3.76 (m, 2H), 2.93-2.87 (m, 4H), 2.62-2.54 (m, 2H), 1.22 (d, 3H, J= 6.0 Hz). 223 1 ¹H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.31 (s, 2H),538 8.19 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.35-7.22 (m, 4H), 7.17 (tt,J = 5.5, 2.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 2H), 4.77 (d, J = 4.7 Hz,1H), 4.05 (q, J = 7.3 Hz, 1H), 3.78 (q, J = 7.0, 6.4 Hz, 8H), 3.62-3.47(m, 2H), 3.43-3.35 (m, 1H), 2.62-2.52 (m, 1H), 2.42 (dd, J = 11.4, 9.0Hz, 1H), 1.86 (dt, J = 12.5, 4.1 Hz, 1H), 1.73 (dt, J = 13.0, 3.8 Hz,1H), 1.56 (d, J = 7.3 Hz, 4H), 1.29-1.17 (m, 1H). 224 1 ¹H NMR (400 MHz,DMSO-d6) δ 9.43 (s, 1H), 8.31 (s, 2H), 538 8.19 (s, 1H), 7.49 (d, J =8.3 Hz, 2H), 7.36-7.23 (m, 4H), 7.23-7.13 (m, 1H), 6.86 (d, J = 8.6 Hz,2H), 4.77 (d, J = 4.7 Hz, 1H), 4.05 (q, J = 7.2 Hz, 1H), 3.78 (m, 8H),3.64-3.46 (m, 2H), 2.56 (td, J = 11.7, 3.0 Hz, 1H), 2.42 (dd, J = 11.4,9.0 Hz, 1H), 1.87 (m, 1H), 1.73 (m, 1H), 1.63-1.45 (m, 4H), 1.22 (tdd, J= 12.1, 9.5, 4.1 Hz, 1H). 225 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.42 (s,1H), 8.30 (s, 2H), 538 8.18 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.24 (tt,J = 19.9, 7.5 Hz, 5H), 6.85 (d, J = 9.3 Hz, 2H), 4.38 (s, 1H), 3.98-3.65(m, 10H), 2.97 (d, J = 6.1 Hz, 2H), 2.89-2.80 (m, 2H), 1.78 (m, 1H),1.57-1.40 (m, 3H), 1.16 (s, 3H). 226 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.42(s, 1H), 8.31 (s, 2H), 539 8.19 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H),7.34-7.14 (m, 5H), 6.86 (d, J = 8.5 Hz, 2H), 4.38 (s, 1H), 3.79 (s,10H), 2.98 (d, J = 6.5 Hz, 2H), 2.90-2.79 (m, 2H), 1.79 (dt, J = 11.4,6.1 Hz, 2H), 1.59-1.52 (m, 1H), 1.47 (t, J = 6.1 Hz, 2H), 1.16 (s, 3H).227 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.31 (s, 2H), 538 8.19(s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.33-7.15 (m, 5H), 6.86 (d, J = 8.3Hz, 2H), 4.38 (s, 1H), 3.79 (br.s, 10H), 2.97 (dt, J = 7.4, 3.9 Hz, 2H),2.89-2.80 (m, 2H), 1.79 (dt, J = 11.4, 5.9 Hz, 1H), 1.54 (dt, J = 13.5,6.6 Hz, 1H), 1.47 (t, J = 6.0 Hz, 2H), 1.16 (s, 3H). 228 1 ¹H NMR (400MHz, DMSO-d6) δ 8.74 (s, 1H), 8.09 (s, 1H), 538 7.63 (s, 1H), 7.30-7.11(m, 6H), 6.81-6.67 (m, 2H), 6.29 (s, 2H), 3.68 (m, 10H), 3.01 (dd, J =6.6, 3.5 Hz, 4H), 2.84 (dd, J = 6.3, 3.6 Hz, 4H), 2.12 (s, 3H). 229 1 ¹HNMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.22 (s, 1H), 539 7.64 (s, 1H),7.40 (d, J = 7.2 Hz, 2H), 7.31-7.13 (m, 5H), 7.01 (d, J = 8.4 Hz, 1H),6.31 (s, 2H), 4.47 (br.s, 1H), 3.83-3.53 (m, 14H), 2.73 (br.s, 4H), 2.57(br.s, 2H). 221 3 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.58 (br. s., 1H),8.32 (s, 2H), 8.24 (s, 1H), 7.41 (d, 1H, J = 7.5 Hz), 7.40 (s, 1H), 7.29(d, 2H, J = 7.5 Hz), 7.23 (d, 2H, J = 7.5 Hz), 7.19 (d, 1H, J = 7.5 Hz),7.01 (d, 1H, J = 7.5 Hz), 4.39 (d, 1H, J = 4.0 Hz), 3.89-3.79 (m, 11H),3.56 (s, 2H), 2.74-2.67 (m, 4H), 2.44-2.31 (m, 2H), 1.07 (d, 3H, J = 5.5Hz). 222 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.31 (s, 2H), 5388.19 (s, 1H), 7.51 (s, 2H), 7.34-7.27 (m, 2H), 7.27-7.16 (m, 3H), 6.88(d, J = 8.5 Hz, 2H), 4.95-4.73 (m, 2H), 4.47 (dd, J = 24.2, 13.2 Hz,2H), 4.34 (d, J = 4.2 Hz, 2H), 3.78 (d, J = 10.8 Hz, 3H), 3.66-3.47 (m,2H), 3.40 (d, J = 12.1 Hz, 1H), 3.27-3.09 (m, 2H), 2.59 (d, J = 10.0 Hz,1H), 2.43 (t, J = 10.2 Hz, 1H), 1.88 (d, J = 12.4 Hz, 1H), 1.73 (dd, J =11.1, 7.2 Hz, 1H), 1.53 (d, J = 12.8 Hz, 1H), 1.31-1.17 (m, 2H), 1.04(d, J = 6.3 Hz, 10H). 231 1 ¹H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H),8.19 (s, 1H), 539 7.65 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.35-7.11 (m,4H), 6.87 (d, J = 8.5 Hz, 2H), 6.31 (s, 2H), 4.78 (d, J = 4.7 Hz, 1H),3.93-3.46 (m, 12H), 3.40 (d, J = 11.8 Hz, 1H), 1.88 (d, J = 12.8 Hz,1H), 1.79-1.68 (m, 1H), 1.60-1.45 (m, 1H), 1.31-1.16 (m, 1H) - two peaksare obscured on either side of DMSO signal. 232 2 ¹H NMR (400 MHz,DMSO-d6) δ 9.43 (s, 2H), 8.32 (s, 3H), 540 7.49 (d, J = 8.5 Hz, 2H),7.38-7.07 (m, 5H), 6.88 (d, J = 8.7 Hz, 2H), 4.63-4.26 (m, 2H), 3.78 (m,10H), 3.61 (m, 1H), 3.21-2.91 (m, 3H), 1.88-1.49 (m, 2H), 1.04 (d, J =6.1 Hz, 1H). 234 4 ¹H-NMR (400 MHz, DMSO-d6) δ ppm 9.46 (br. s., 1H),8.38 (s, 540 2H), 8.20 (s, 1H), 7.53 (d, 2H, J = 8.0 Hz), 7.44 (d, 2H, J= 8.0 Hz), 7.33-7.29 (m, 2H), 7.22-7.18 (m, 1H), 6.91 (d, 2H, J = 8.0Hz), 5.80 (s, 1H), 3.81 (br. s., 8H), 3.73 (t, 4H, J = 4.8 Hz), 3.04 (t,4H, J = 4.8 Hz), 1.82 (s, 3H). 235 4 ¹H-NMR (400 MHz, DMSO-d6) δ ppm9.47 (br. s., 1H), 8.38 (s, 540 2H), 8.21 (s, 1H), 7.53 (d, 2H, J = 8.0Hz), 7.45-7.43 (m, 2H), 7.33-7.29 (m, 2H), 7.22-7.19 (m, 1H), 6.91 (d,2H, J = 8.0 Hz), 5.80 (s, 1H), 3.81 (br. s., 8H), 3.73 (t, 4H, J = 4.8Hz), 3.04 (t, 4H, J = 4.8 Hz), 1.82 (s, 3H). 236 3 ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.53 (br. s., 1H), 8.26 (s, 1H), 8.19 (s, 2H), 7.53-7.51(m, 2H), 7.41-7.40 (m, 2H), 7.30-7.29 (m, 2H), 7.24-7.15 (m, 3H),3.86-3.73 (m, 11H), 3.39-3.30 (m, 3H), 3.07-3.05 (m, 1H), 2.81-2.79 (m,1H), 2.32-2.22 (m, 1H), 1.96-1.75 (m, 3H). 237 3 ¹H NMR (400 MHz,DMSO-d6) δ 9.67 (s, 1H), 8.31 (s, 2H), 541 8.25 (s, 1H), 7.55 (d, J =15.1 Hz, 1H), 7.40 (s, 1H), 7.32-7.14 (m, 5H), 6.99 (t, J = 9.4 Hz, 1H),3.88-3.71 (m, 17H), 2.96 (t, J = 4.7 Hz, 4H), 2.25 (s, 3H) - one peak ispartially obscured by water. 238 2 ¹H NMR (400 MHz, DMSO-d6) δ 9.05 (s,1H), 8.29 (s, 2H), 542 8.15 (s, 1H), 7.43-7.11 (m, 6H), 6.87 (dd, J =12.5, 2.7 Hz, 1H), 6.75 (dd, J = 9.1, 2.7 Hz, 1H), 4.28-4.17 (m, 1H),3.76 (m, 10H), 3.07 (d, J = 11.4 Hz, 1H), 2.75 (dt, J = 12.4, 4.0 Hz,1H), 2.01 (s, 1H), 1.71-1.59 (m, 1H), 1.54-1.37 (m, 2H) - one peakobscured by DMSO signal. 239 2 ¹H-NMR (500 MHz, CDCl3) δ ppm 8.25 (s,1H), 8.17 (s, 2H), 542 7.41 (d, 2H, J = 8.5 Hz), 7.13-7.10 (m, 2H),7.00-6.93 (m, 4H), 3.96-3.86 (m, 9H), 3.78 (s, 2H), 3.28-3.24 (m, 1H),3.08-3.03 (m, 3H), 2.48-2.27 (br, 1H), 1.95-1.91 (m, 1H), 1.84-1.76 (m,2H), 1.72-1.60 (m, 2H). 240 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H),8.31 (s, 2H), 542 8.20 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.32-7.23 (m,2H), 7.16-7.07 (m, 2H), 6.87 (d, J = 8.5 Hz, 2H), 4.78 (d, J = 4.7 Hz,1H), 3.80 (m, 10H), 3.57 (m, 2H), 2.57 (td, J = 11.8, 3.2 Hz, 1H), 2.43(dd, J = 11.3, 9.0 Hz, 1H), 1.87 (dt, J = 12.6, 4.3 Hz, 1H), 1.73 (ddd,J = 11.6, 7.9, 4.0 Hz, 1H), 1.60-1.45 (m, 1H), 1.29-1.17 (m, 1H). 241 3This spectrum contains some rotomers in the aromatic region: ¹H 542 NMR(400 MHz, DMSO-d6) δ 9.62, 9.48 (s, 1H), 8.31, 8.27 (s, 2H), 8.15 (s,1H), 7.82 (s, 1H), 7.48, 7.47 (s, 1H), 7.36-7.12 (m, 5H), 4.22-4.05 (m,2H), 3.79 (m, 10H), 3.54-3.39 (m, 2H), 2.75-2.58 (m, 2H), 2.28 (q, J =7.2 Hz, 2H), 2.02-1.89 (m, 1H), 1.72 (t, J = 10.3 Hz, 1H), 0.96 (t, J =7.1 Hz, 3H). 242 3 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.00-8.74 (m, 1H),8.31 (s, 2H), 8.14 (s, 1H), 7.58-7.41 (m, 1H), 7.30-7.27 (m, 2H),7.24-7.17 (m, 3H), 4.83 (br. s., 1H), 4.60-4.31 (m, 3H), 4.02-3.96 (m,2H), 3.78 (s, 2H), 3.69-3.64 (m, 2H), 3.37-3.34 (m, 2H), 3.21-3.13 (m,2H), 3.02-2.96 (m, 1H), 2.73-2.59 (m, 3H), 2.41-2.37 (m, 1H), 2.17, 2.12(m, 3H), 1.15-1.01 (br, 3H). 243 1 ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.98,8.73 (s, s, 1H), 8.31 (s, 2H), 8.14 (s, 1H), 7.53, 7.39 (s, s, 1H), 7.27(br. s., 4H), 7.19-7.17 (m, 1H), 4.05-3.97 (m, 3H), 3.78-3.66 (m, 10H),2.73-2.56 (m, 4H), 2.40-2.35 (m, 1H), 2.14-2.07 (m, 3H), 1.55 (d, 3H, J= 6.8 Hz). 244 4 ¹H-NMR (500 MHz, CDCl₃) δ ppm 8.33, 8.23 (br. s., s,3H), 7.85, 7.76 (s, s, 1H), 7.58, 7.51 (s, s, 1H), 7.30-7.26 (m, 2H),7.26-7.24 (m, 1H), 7.20-7.18 (m, 2H), 7.71, 6.60 (br. s., br. s., 1H),4.16-4.15 (m, 2H), 3.92-3.88 (m, 10H), 3.67-3.65 (m, 1H), 3.00-2.98 (m,1H), 2.88-2.87 (m, 2H), 2.61-2.55 (m, 1H), 1.67 (s, 6H). 245 1 ¹H-NMR(500 MHz, DMSO-d₆) δ ppm 8.97, 8.71 (s, s, 1H), 8.13 (d, 1H, J = 6.5Hz), 7.64 (s, 1H), 7.54, 7.40 (s, s, 1H), 7.28-7.17 (m, 5H), 6.31 (s,2H), 4.01-3.98 (m, 2H), 3.76-3.65 (m, 13H), 2.74-2.60 (m, 3H), 2.41-2.36(m, 1H), 2.16, 2.12 (m, 3H). 246 1 1H-NMR (500 MHz, DMSO-d₆) δ ppm 9.62,9.47 (s, s, 1H), 8.28, 8.18 (s, s, 1H), 8.02 (s, 1H), 7.83 (s, 1H),7.50, 7.47 (s, s, 1H), 7.26 (t, 2H, J = 7.5 Hz), 7.19-7.15 (m, 3H),4.13-4.01 (m, 2H), 3.87 (s, 3H), 3.87-3.65 (m, 12H), 3.42-3.36 (m, 1H),2.72-2.57 (m, 3H), 2.37-2.33 (m, 1H). 247 1 ¹H-NMR (500 MHz, DMSO-d₆) δppm 9.66-9.52 (m, 1H), 8.32 (d, 2H, J = 7.5 Hz), 8.29, 8.16 (s, s, 1H),8.02-7.83 (m, 1H), 7.54-7.48 (m, 1H), 7.30 (t, 2H, J = 7.5 Hz), 7.24 (d,2H, J = 7.0 Hz), 7.20 (t, 1H, J = 7.5 Hz), 4.98-4.28 (m, 5H), 4.09-4.04(m, 2H), 3.80 (s, 2H), 3.72-3.67 (m, 2H), 3.34-3.07 (m, 4H), 2.70-2.56(m, 3H), 2.38-2.32 (m, 2H). 248 2 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm9.64-9.49 (m, 1H), 8.31 (d, 2H, J = 7.0 Hz), 8.28, 8.15 (s, s, 1H),8.00, 7.83 (s, s, 1H), 7.53, 7.49, 7.47 (s, s, s, 1H), 7.30 (t, 2H, J =7.5 Hz), 7.24 (d, 2H, J = 7.0 Hz), 7.19 (t, 1H, J = 7.5 Hz), 4.95-3.99(m, 7H), 3.80 (s, 2H), 3.72-3.65 (m, 2H), 3.46-3.36 (m, 2H), 3.28-3.03(m, 2H), 2.70-2.54 (m, 3H), 2.38-2.32 (m, 2H). 249 1 ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 9.64, 9.51 (s, s, 1H), 8.33 (s, 2H), 8.28, 8.16 (s, s,1H), 7.83 (s, 1H), 7.49, 7.47 (s, s, 1H), 7.22-7.18 (m, 1H), 6.82-6.75(m, 3H), 4.11-4.03 (m, 2H), 3.83-3.65 (m, 11H), 3.43-3.32 (m, 6H),2.72-2.57 (m, 3H), 2.38-2.32 (m, 1H). 250 4 ¹H-NMR (500 MHz, DMSO-d₆) δppm 9.65, 9.52 (s, s, 1H), 8.38 (s, 2H), 8.28, 8.15 (s, s, 1H), 7.82 (s,1H), 7.49-7.43 (m, 3H), 7.32-7.29 (m, 2H), 7.22-7.19 (m, 1H), 5.83 (s,1H), 4.11-4.02 (m, 2H), 3.83-3.78 (m, 8H), 3.71-3.64 (m, 2H), 3.40-3.36(m, 1H), 2.70-2.56 (m, 3H), 2.36-2.32 (m, 2H), 1.81 (s, 3H). 251 5¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.80-9.66 (m, 2H), 8.55 (s, 2H), 8.35(s, 1H), 7.73, 7.72 (s, s, 2H), 7.35, 7.34 (s, s, 2H), 7.29-7.23 (m,2H), 7.17-7.14 (m, 1H), 7.06-7.02 (m, 1H), 4.77-7.73 (m, 1H), 4.09 (dd,1H, J = 12.0, 3.0 Hz), 3.97-3.90 (m, 9H), 3.35 (d, 1H, J = 11.5 Hz),3.23 (d, 1H, J = 13.0 Hz), 3.12-2.95 (m, 2H). 252 3 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 9.78 (br. s., 1H), 8.33 (s, 2H), 8.29 (s, 1H), 7.73 (d,2H, J = 8.5 Hz), 7.35 (d, 2H, J = 8.5 Hz), 7.30 (t, 2H, J = 7.5 Hz),7.24 (d, 2H, J = 7.0 Hz), 7.20 (t, 1H, J = 7.0 Hz), 4.35 (s, 2H),3.85-3.81 (m, 10H), 2.72 (s, 6H). 253 2 ¹H NMR (400 MHz, DMSO-d6) δ9.64, 9.51 (s, 1H, rotamer), 548 8.50 (s, 2H), 8.17 (s, 1H), 7.83 (s,1H), 7.49 (s, 1H), 7.24-6.82 (m, 4H), 4.93 (s, 2H), 4.18-3.97 (m, 2H),3.96-3.55 (m, 11H), 2.78-2.57 (m, 4H), 2.43-2.21 (m, 1H). 254 4 ¹H-NMR(500 MHz, CDCl₃) δ ppm 8.82, 8.39 (s, s, 2H), 8.32, 8.22 (br. s., br.s., 1H), 7.83-7.74 (m, 1H), 7.61-7.59 (m, 1H), 7.52-7.45 (m, 5H),7.30-7.27 (br, 1H), 4.14-4.13 (m, 2H), 3.95-3.82 (m, 11H), 3.62-3.58 (m,1H), 2.94-2.81 (m, 3H), 2.58-2.54 (m, 1H). 255 5 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 9.68, 9.55 (s, s, 1H), 550 8.55 (s, 2H), 8.30, 8.18 (s,s, 1H), 7.83 (s, 1H), 7.50, 7.47 (s, s, 1H), 7.29-7.25 (m, 2H), 7.15(td, 1H, J = 8.5, 2.0 Hz), 7.04 (t, J = 8.0 Hz, 1H), 4.14-4.03 (m, 2H),3.94-3.82 (m, 8H), 3.72-3.65 (m, 2H), 3.39 (td, J = 11.0 Hz, J = 3.0 Hz1H), 2.71-2.58 (m, 3H), 2.37-2.31 (m, 2H). 256 5 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 9.67, 9.53 (s, s, 1H), 550 8.54 (s, 2H), 8.30, 8.17 (s,s, 1H), 7.83 (s, 1H), 7.50, 7.47 (s, s, 1H), 7.28-7.25 (m, 2H), 7.17 (t,2H, J = 8.0 Hz), 4.11-4.03 (m, 2H), 3.94-3.88 (m, 8H), 3.72-3.64 (m,2H), 3.41-3.36 (m, 1H), 2.71-2.60 (m, 3H), 2.37-2.33 (m, 2H). 257 5¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.67, 9.54 (s, s, 1H), 8.56 (s, 2H),8.30, 8.18 (s, s, 1H), 7.83 (s, 1H), 7.51, 7.47 (s, s, 1H), 7.38-7.33(m, 1H), 7.04-6.96 (m, 3H), 4.14-4.03 (m, 2H), 3.95-3.90 (m, 8H),3.72-3.65 (m, 2H), 3.42-3.37 (m, 1H), 2.71-2.60 (m, 3H), 2.37-2.31 (m,2H). 258 5 ¹H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.40 (s, 1H), 5518.18 (s, 1H), 7.82 (s, 1H), 7.57-7.45 (m, 3H), 7.31-7.20 (m, 2H), 4.07(m, 2H), 3.90 (m, 8H), 3.75-3.63 (m, 3H), 3.47-3.24 (m, 3H), 2.74-2.54(m, 3H), 2.40-2.28 (m, 1H). 259 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.65 (s,1H), 8.30 (s, 2H), 551 8.25 (s, 1H), 8.20 (s, 1H), 7.82 (s, 2H), 7.46(d, J = 8.1 Hz, 1H), 7.33-7.12 (m, 6H), 6.90 (d, J = 7.5 Hz, 1H),3.87-3.75 (m, 16H), 2.75-2.63 (m, 3H), 2.65-2.54 (m, 1H), 2.45-2.35 (m,2H), 2.29-2.20 (m, 2H), 2.08 (s, 6H), 1.89-1.81 (m, 1H), 1.66-1.55 (m,1H). One peak is obscured by water peak and cannot be accuratelyintegrated 260 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.30 (s, 2H),551 8.24 (s, 1H), 7.82 (s, 1H), 7.45 (s, 1H), 7.31-7.25 (m, 3H),7.25-7.13 (m, 4H), 6.90 (d, J = 7.5 Hz, 1H), 3.92-3.67 (m, 10H), 3.57(d, J = 13.1 Hz, 1H), 3.43 (d, J = 13.0 Hz, 1H), 2.74-2.54 (m, 3H),2.44-2.32 (m, 1H), 2.28-2.16 (m, 1H), 2.05 (s, 6H), 1.90-1.78 (m, 1H),1.66-1.52 (m, 1H). 261 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.30(s, 2H), 551 8.24 (s, 1H), 7.81 (s, 1H), 7.45 (s, 1H), 7.32-7.23 (m,3H), 7.26-7.13 (m, 4H), 6.90 (d, J = 7.6 Hz, 1H), 3.91-3.70 (m, 10H),3.57 (d, J = 13.0 Hz, 1H), 3.44 (d, J = 13.0 Hz, 1H), 2.77-2.54 (m, 3H),2.46-2.34 (m, 1H), 2.30-2.17 (m, 1H), 2.08 (s, 6H), 1.92-1.78 (m, 1H),1.68-1.53 (m, 1H). 262 3 ¹H-NMR (500 MHz, CDCl₃) δ ppm 8.27 (s, 1H),8.21 (s, 2H), 7.31-7.28 (m, 3H), 7.25-7.08 (m, 5H), 3.91-3.88 (m, 8H),3.82-3.80 (m, 4H), 2.94-2.88 (m, 4H), 2.52 (s, 2H), 1.22 (s, 6H). 263 4¹H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.25 (s, 2H), 552 8.19 (s,1H), 7.49 (d, J = 8.3 Hz, 2H), 7.35-7.23 (m, 4H), 7.23-7.13 (m, 1H),6.86 (d, J = 8.6 Hz, 2H), 4.77 (s, 1H), 3.88-3.70 (m, 8H), 3.65-3.46 (m,3H), 2.62-2.53 (m, 1H), 2.46-2.37 (m, 1H), 1.92-1.82 (m, 1H), 1.72 (dd,J = 10.4, 6.6 Hz, 1H), 1.63 (s, 6H), 1.52 (m, 1H), 1.24 (dt, J = 13.2,6.2 Hz, 2H). 265 1 ¹H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.20 (s,1H), 553 7.64 (s, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.31-7.11 (m, 5H), 6.89(d, J = 8.5 Hz, 2H), 6.30 (s, 2H), 3.94 (dd, J = 9.6, 5.4 Hz, 1H),3.85-3.58 (m, 10H), 2.97 (br.s, 1H), 2.37 (s, 3H), 2.21 (br.s, 1H), 1.96(t, J = 10.3 Hz, 1H), 1.76-1.52 (m, 3H) one peak obscured by DMSOsignal. 266 1 ¹H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.20 (s, 1H),553 7.64 (s, 1H), 7.56 (dd, J = 9.1, 3.0 Hz, 2H), 7.34-7.10 (m, 5H),6.88 (d, J = 8.5 Hz, 2H), 6.30 (s, 2H), 3.93 (dd, J = 9.6, 5.3 Hz, 1H),3.72 (dd, J = 41.7, 13.4 Hz, 10H), 2.96 (s, 1H), 2.36 (s, 3H), 2.19 (s,1H), 1.95 (dq, J = 12.4, 8.2 Hz, 1H), 1.74-1.62 (m, 2H), 1.63-1.50 (m,1H) one peak obscured by DMSO signal. 267 4 ¹H-NMR (400 MHz, DMSO-d6) δppm 9.65, 9.50 (s, s, 1H), 560 8.27 (s, 2H), 8.16 (s, 1H), 7.83 (s, 1H),7.50, 7.47 (s, s, 1H), 7.30 (dd, 2H, J = 8.8, 6.0 Hz), 7.14-7.09 (m,2H), 4.11-4.03 (m, 2H), 3.84-3.66 (m, 10H), 2.72-2.57 (m, 4H), 2.35-2.32(m, 2H), 1.63 (s, 6H). 268 3 ¹H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H),8.31 (s, 2H), 562 8.25 (s, 1H), 7.42 (d, J = 6.3 Hz, 2H), 7.33-7.15 (m,5H), 7.04 (d, J = 8.7 Hz, 1H), 3.89-3.71 (m, 12H), 2.90 (t, J = 5.9 Hz,2H), 2.75 (t, J = 5.7 Hz, 2H) - one peak is obscured by water signal.269 4 ¹H-NMR (400 MHz, CDCl3) δ ppm 8.36 (s, 2H), 8.20 (br. s., 1H), 5627.75 (br. s., 1H), 7.57 (br. s., 1H), 7.42-7.38 (m, 2H), 7.05-7.00 (m,2H), 4.15-4.11 (m, 2H), 3.90-3.84 (m, 11H), 3.62-3.56 (m, 1H), 2.93-2.79(m, 2H), 2.58-2.53 (m, 1H), 1.93 (s, 3H). 270 4 ¹H-NMR (400 MHz,DMSO-d6) δ ppm 9.64, 9.50 (s, s, 1H), 562 8.38 (s, 2H), 8.29, 8.16 (s,s, 1H), 7.83 (s, 1H), 7.49-7.44 (m, 3H), 7.14-7.10 (m, 2H), 5.89 (s,1H), 4.11-4.02 (m, 2H), 3.84-3.66 (m, 10H), 2.71-2.57 (m, 3H), 2.38-2.32(m, 1H), 1.81 (s, 3H). 271 1 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.00, 8.75(s, s, 1H), 8.30 (s, 2H), 8.25 (s, 1H), 8.15, 8.13 (s, s, 1H), 7.55,7.41 (s, s, 1H), 7.28-7.25 (m, 2H), 7.13-7.10 (m, 2H), 4.07-3.98 (m,3H), 3.78-3.70 (m, 13H), 3.41-3.37 (m, 1H), 2.80-2.62 (m, 3H), 2.44-2.42(m, 1H), 2.16, 2.11 (s, s, 3H). 272 1 ¹H-NMR (500 MHz, DMSO-d₆) δ ppm8.99, 8.75 (s, s, 1H), 8.29 (s, 2H), 8.20 (s, 1H), 8.15, 8.13 (s, s,1H), 7.54, 7.40 (s, s, 1H), 7.33-7.25 (m, 2H), 7.17-7.12 (m, 2H),4.03-3.96 (m, 2H), 3.81-3.69 (m, 12H), 3.45-3.33 (m, 1H), 2.78-2.62 (m,3H), 2.45-2.36 (m, 2H), 2.15, 2.11 (s, s, 3H). 273 5 ¹H-NMR (500 MHz,DMSO-d₆) δ ppm 9.03, 8.78 (s, s, 1H), 8.53 (s, 2H), 8.16-8.15 (m, 1H),7.29, 7.24 (s, s, 1H), 7.27-7.24 (m, 2H), 7.19-7.15 (m, 2H), 4.02-3.96(m, 2H), 3.86-3.64 (m, 10H), 3.37-3.35 (br. s., 2H), 2.74-2.56 (m, 3H),2.41-2.37 (m, 1H), 2.17, 2.12 (s, s, 3H). 275 4 ¹H-NMR (400 MHz, CDCl3)δ ppm 8.35 (s, 2H), 8.25 (s, 1H), 571 7.43-7.35 (m, 4H), 7.00 (t, 2H, J= 8.8 Hz), 6.94 (d, 2H, J = 8.8 Hz), 7.00-6.93 (br., 1H), 3.96-3.93 (m,1H), 3.92-3.80 (m, 8H), 3.28-3.24 (m, 1H), 3.09-3.03 (m, 3H), 2.35-2.15(br., 1H), 1.95-1.91 (m, 1H), 1.83 (s, 3H), 1.82-1.70 (m, 3H). 276 4¹H-NMR (400 MHz, CDCl3) δ ppm 8.34 (s, 2H), 8.20 (br. s., 1H), 576 7.71(br. s., 0.5H), 7.41-7.38 (m, 2H), 7.04-6.99 (m, 2H), 6.50 (br. s.,0.5H), 4.09-4.08 (m, 2H), 3.87-3.85 (m, 10H), 3.62-3.56 (m, 1H),2.98-2.83 (m, 3H), 2.65-2.59 (m, 1H), 2.22 (s, 3H), 1.92 (s, 3H). 277 4¹H-NMR (400 MHz, CDCl3) δ ppm 8.34 (s, 2H), 8.20 (br. s., 1H), 576 7.71(br. s., 0.5H), 7.41-7.38 (m, 2H), 7.04-6.99 (m, 2H), 6.50 (br. s.,0.5H), 4.09-4.08 (m, 2H), 3.87-3.85 (m, 10H), 3.63-3.57 (m, 1H),2.99-2.84 (m, 3H), 2.68-2.60 (m, 1H), 2.22 (s, 3H), 1.92 (s, 3H).Biochemical Activity of Compounds

In order to assess the activity of chemical compounds against therelevant kinase of interest, the Caliper LifeSciences electrophoreticmobility shift technology platform is used. Fluorescently labeledsubstrate peptide is incubated in the presence of kinase and ATP so thata reflective proportion of the peptide is phosphorylated. At the end ofthe reaction, the mix of phosphorylated (product) and non-phosphorylated(substrate) peptides are passed through the microfluidic system of theCaliper EZ Reader 2, under an applied potential difference. The presenceof the phosphate group on the product peptide provides a difference inmass and charge between those of the substrate peptide, resulting in aseparation of the substrate and product pools in the sample. As thepools pass a LEDS within the instrument, these pools are detected andresolved as separate peaks. The ratio between these peaks thereforereflects the activity of the chemical matter at that concentration inthat well, under those conditions.

Kit wild type assay at Km: In each well of a 384-well plate, 0.2 ng/ulfinal (2 nM) of wild type Kit (Carna Bioscience 08-156) was incubated ina total of 12.5 ul of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mMMgCl2, 1 mM DTT) with 1 uM Srctide (5-FAM-GEEPLYWSFPAKKK-NH2) and 400 uMATP at 25 C for 90 minutes in the presence or absence of a dosedconcentration series of compound (1% DMSO final concentration). Thereaction was stopped by the addition of 70 ul of Stop buffer (100 mMHEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3(Caliper Lifesciences)). The plate was then read on a Caliper EZReader 2(protocol settings: −1.9 psi, upstream voltage −700, downstream voltage−3000, post sample sip 35 s). Data was normalized to 0% and 100%inhibition controls and the IC50 or EC50 calculated using a 4-parameterfit using GraphPad Prism.

Kit D816V assay at Km: In each well of a 384-well plate, 0.04 ng/ul (0.5nM) of D816V Kit (Carna Bioscience 08-156) was incubated in a total of12.5 ul of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl2, 1mM DTT) with 1 uM Srctide (5-FAM-GEEPLYWSFPAKKK-NH2) and 15 uM ATP at 25C for 90 minutes in the presence or absence of a dosed concentrationseries of compound (1% DMSO final concentration). The reaction wasstopped by the addition of 70 ul of Stop buffer (100 mM HEPES pH 7.5,0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (CaliperLifesciences)). The plate was then read on a Caliper EZReader 2(protocol settings: −1.9 psi, upstream voltage −700, downstream voltage−3000, post sample sip 35 s). Data was normalized to 0% and 100%inhibition controls and the IC50 or EC50 calculated using a 4-parameterfit using GraphPad Prism.

PDGFRA D842V assay at Km: In each well of a 384-well plate, 0.7 ng/ul (8nM) of PDGFRA D842V (ProQinase 0761-0000-1) was incubated in a total of12.5 ul of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl2, 1mM DTT) with 1 uM CSKtide (5-FAM-KKKKEEIYFFF-NH2) and 15 uM ATP at 25 Cfor 90 minutes in the presence or absence of a dosed concentrationseries of compound (1% DMSO final concentration). The reaction wasstopped by the addition of 70 ul of Stop buffer (100 mM HEPES pH 7.5,0.015% Brij 35, 35 mM EDTA and 0.2% of Coating Reagent 3 (CaliperLifesciences)). The plate was then read on a Caliper EZReader 2(protocol settings: −1.9 psi, upstream voltage −500, downstream voltage−3000, post sample sip 38 s). Data was normalized to 0% and 100%inhibition controls and the IC₅₀ or EC₅₀ calculated using a 4-parameterfit using GraphPad Prism.

Cellular Activity of Compound

HMC1.2 autophosphorylation assay:

10,000 HMC1.2 cells were incubated in 22 ul culture media (phenol-redfree IMDM, no serum) in each well of a 384-well plate and serum starvedovernight in a tissue culture incubator (5% CO₂, 37° C.). A 10-pointdose concentration series of compound (25 uM-95.4 pM) were then added tothe cells in a volume of 3.1 ul to each well (0.25% DMSO finalconcentration). After 90 minutes, 6 ul of 5×AlphaLISA Lysis Buffer(Perkin Elmer) supplemented with a protease and phosphatase inhibitorcocktail (Cell Signaling Technologies) was added to each well and shakenat 450 rpm for 15 minutes at 4° C. 10 ul of phospho-Y719 c-Kit and totalc-Kit antibodies (15 nM final concentration, Cell SignalingTechnologies) and 50 ug/ml AlphaLISA rabbit acceptor beads (PerkinElmer) were added to each well and shaken at 300 rpm at room temperaturefor 2 hours. 10 ul of 100 ug/ml streptavidin donor beads (Perkin Elmer)were added to each well, blocked from light with aluminum adhesive andshaken at 300 rpm at room temperature for 2 hours. Fluorescence signalwas obtained on Envision (Perkin Elmer) by AlphaScreen 384 well HTSprotocol. Data was normalized to 0% and 100% inhibition controls and theIC50 was calculated using Four Parameter Logistic IC50 curve fitting.

The Table below shows the activity of compounds in a Mast cell leukemiacell line, HMC 1.2. This cell line contains Kit mutated at positionsV560G and D816V resulting in constitutive activation of the kinase. Thefollowing compounds were tested in an assay to measure direct inhibitionof Kit D816V kinase activity by assaying Kit autophosphorylation attyrosine 719 on the Kit protein.

The Table below shows the activity of compounds described herein,against wild-type Kit, mutant Kit (the D816V mutant), and mutan PDFGRA(the D852V mutant). In the Table below, for KIT D816V activity andPDGFRA D842V, the following designations are used: <1.00 nM=A; 1.01-10.0nM=B; 10.01-100.0 nM=C; >100 nM=D; and ND=not determined. For wild-typeKit activity, the following designations are used: <10 nM=A; 11-100nM=B; 100-1000 nM=C; >1000 nM=D; and ND=not determined.

In the Table below, for cellular activity, the following designationsare used: <10 nM=A; 10.01-100 nM=B; 100.01-1000 nM=C; 1000-10000nM=D, >10000.01 nM=E; and ND=not determined.

Compound D816V WT PDFGRA Cellular Numer KIT KIT D842V Activity 1 D ND 2B ND D 3 D ND 4 A A A B 5 B C D 6 D ND E 7 B B D 8 C ND 9 C C 10 A B B C11 C ND 12 A A A A 13 A A B 14 A B C 15 A B A B 16 A B C 17 B ND D 18 DND E 19 C ND E 20 A ND B 21 B ND C 22 B C C 23 B B C 24 B B C 25 A B A B26 B B C 27 B ND B 28 A ND B 29 A B 30 A B A B 31 A A B 32 B ND B 33 BND B 34 C ND D 35 D ND E 36 A A 37 D D 38 A B 39 A B 40 C B 41 A A B 42B B B 43 A B B B 44 B B B B 45 B ND B 46 A A B B 47 A B A B 48 A A A B49 A B B 50 B B D 51 A B B 52 A A A B 53 A A A B 54 B C 55 A ND B 56 A AB 57 A B B 58 B ND C 59 D C 60 A B B 61 A A A B 62 A ND B 63 D ND 64 A BB 65 A ND B 66 A ND B 67 C ND 68 B B A B 69 A A A A 70 B ND C 71 A ND B72 A ND B 73 A A A A 74 A B B 75 A A A B 76 A A B 77 B ND B 78 A ND B 79B B 80 B ND B 81 A ND B 82 A ND B 83 A A A B 84 A A B 85 A B B 86 A B B87 B ND B 88 A B A B 89 A B C 90 C ND 91 B ND D 92 A B 93 A B 94 B B B95 A B D 96 A B C 97 A ND B 98 A A A B 99 B ND A 100 A ND B 101 A ND A A102 A A A B 103 B B C 104 B B C 105 A B C 106 A B B C 107 A ND B 108 AND B 109 A ND A 110 A ND B 111 B ND B 112 B ND C 113 B ND C 114 B C C115 A A B 116 A A A B 117 A A A B 118 A A B 119 A A 120 A B 121 A B 122A B 123 A A A A 124 A A A B 125 A ND B 126 B ND C 127 A A B 128 B B C129 B ND B 130 B ND B 131 B ND B 132 A ND B 133 A ND B 134 A ND B 135 BND B 136 B ND C 137 B ND B 138 A ND B 139 B ND B 140 A 141 B ND B 142 CND 143 B B C 144 B B C 145 C ND B 146 B ND B 147 B ND C 148 A A A B 149A ND B B 150 B ND B 151 B ND B 152 A ND A 153 A ND B 154 B ND B 155 B NDB 156 A A B 157 A A B C 158 B B C 159 B B C 160 B B C 161 A A B A 162 AA A 163 A A B 164 A A A 165 B C B B 166 A B B A 167 B C B 168 B B B 169A B B 170 A B B 171 B ND B 172 A B 173 B ND B 174 A A A A 175 B ND D 176B ND B 177 B ND B 178 B ND C 179 A A A D 180 A B B 181 A A B 182 A B B183 B ND B 184 B ND B 185 B ND B 186 A ND B 187 B C 188 B B B 189 A ND B190 B ND B 191 A A A 192 A ND A 193 A A 194 C ND 195 A A 196 A ND B 197B ND C 198 A ND A 199 B ND B 200 B ND C 201 A B 202 B ND C 203 B ND B204 B ND C 205 B ND B 206 B ND B 207 A B 208 A A 209 A ND B 210 A ND B211 A ND B B 212 B B C 213 B ND B 214 A B A B 215 A A B 216 A A A 217 AA A 218 A A B 219 A A B 220 A ND B 221 A ND A 222 B ND B 223 B B 224 A B225 B B 226 B B B 227 B B 228 B ND C 229 A ND A 230 B ND D 231 A ND B232 A ND B 233 B ND B 234 B B 235 A A 236 A ND A 237 A B B 238 B ND C239 B B B 240 B A 241 B ND B 242 A ND B 243 B ND B 244 A ND B 245 A ND B246 B ND D 247 C ND 248 A ND B 249 B ND B 250 A ND B 251 B ND C 252 B NDB 253 B ND B 254 B ND 255 A ND B 256 A ND B B 257 B ND C 258 B ND B 259A A A B 260 A A B 261 A A A B 262 A ND B 263 B B B 264 B ND C 265 A A A266 A A A 267 A B 268 B C C 269 A B 270 B 271 B ND B A 272 A ND B 273 BND B 274 C C 275 A B 276 B B 277 A BEfficacy in an In Vivo Model

Compound 165 and Dasatinib were evaluated in a P815 mastocytomaxenograft model. P815 tumor cells (ATCC, Manassas, Va., cat # ATCC®TIB-64) were maintained in vitro as a suspension and monolayer culturein RPMI1640 medium supplemented with 10% fetal calf serum at 37° C. inan atmosphere of 5% CO₂ in air. The tumor cells were sub-cultured twiceweekly by trypsin-EDTA treatment. The cells growing in an exponentialgrowth phase were harvested and counted for tumor inoculation.

Female BALB/c nude mice were used for the study. Each mouse wasinoculated subcutaneously in the right flank with the P815 tumor cells(1×10⁶) in 0.1 ml of PBS for tumor development. The treatments werestarted on day 6 after tumor inoculation when the average tumor sizereached approximately 89 mm³. The testing article and vehicle wereadministrated to the mice according to the regimen shown below.

Dose Dosing Volume Dosing Group n Treatment (mg/kg) (ml/kg) RouteSchedule* 1 13 Vehicle 0 10 p.o. BID × 10 2 10 Dasatinib 25 10 p.o. BID× 10 3 16 Compound 3 10 p.o. BID × 10 165 4 16 Compound 10 10 p.o. BID ×10 165 5 16 Compound 30 10 p.o. BID × 10 165 6 16 Compound 100 10 p.o.BID × 10 165 Note: *BID = twice per day.

Tumor sizes were measured every other day in two dimensions using acaliper, and the volume was expressed in mm³ using the formula: V=0.5a×b² where a and b were the long and short diameters of the tumor,respectively. The tumor size was then used for calculations of both T-Cand T/C values. T-C was calculated with T as the median time (in days)required for the treatment group tumors to reach a predetermined size(e.g., 1000 mm³), and C as the median time (in days) for the controlgroup tumors to reach the same size. The T/C value (in percent) is anindication of antitumor effectiveness; T and C are the mean volumes ofthe treated and control groups, respectively, on a given day.

TGI was calculated for each group using the formula: TGI(%)=[1−(Ti−T0)/(Vi−V0)]×100; Ti is the average tumor volume of atreatment group on a given day, T0 is the average tumor volume of thetreatment group on the day of treatment start, Vi is the average tumorvolume of the vehicle control group on the same day with Ti, and V0 isthe average tumor volume of the vehicle group on the day of treatmentstart. Tumor weight was measured at the endpoint.

A statistical analysis of difference in tumor volume and tumor weightamong the groups was conducted on the data obtained at the besttherapeutic time point after the final dose (the 8^(th) day after thestart of treatment). A one-way ANOVA was performed to compare tumorvolume and tumor weight among groups. All data were analyzed using Prism5.0. p<0.05 was considered to be statistically significant.

Results. The tumor growth curves of different treatment groups are shownin FIG. 1. Data points represent group mean tumor volume, error barsrepresent standard error of the mean (SEM). As shown in FIG. 1, Compound165 was effective in inhibiting tumor growth. Increasing the dose ofCompound 165 enhanced the tumor inhibition efficiency.

Thus, Compound 165, as a single agent, produced an observable antitumoractivity against the P815 mouse mastocytoma cancer xenograft model inthis study.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually indicated to be incorporated byreference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A compound or a pharmaceutically acceptable salt thereofselected from:


2. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of claim 1 or a pharmaceutically acceptable saltthereof.
 3. A method of treating mastocytosis comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof or apharmaceutical composition of claim
 2. 4. The method of claim 3, whereinthe mastocytosis is selected from cutaneous mastocytosis (CM) andsystemic mastocytosis (SM).
 5. The method of claim 3, wherein thesystemic mastocytosis is selected from indolent systemic mastocytosis(ISM), smoldering systemic mastocytosis (SSM), aggressive systemicmastocytosis (ASM), SM with associated hematologic non-mast cell lineagedisease (SM-AHNMD), and mast cell leukemia (MCL).
 6. A method oftreating gastrointestinal stromal tumor, the method comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof or a pharmaceutical composition of claim
 2. 7. A method oftreating acute myeloid leukemia, the method comprising administering toa patient in need thereof a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof or apharmaceutical composition of claim 2.